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Introduction: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap., Methods: A total of 696 consecutive patients with programmed death-ligand 1-high (≥50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of The Cancer Genome Atlas lung adenocarcinoma cohort., Results: Proportion of KRASmut and TP53mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [TP53mut versus wild-type (wt)], p = 0.004; non-G12C: 55.4% versus 39.5%, p = 0.03), progression-free survival (G12C: hazard ratio [HR] = 0.59, p = 0.009, non-G12C: HR = 0.7, p = 0.047), and overall survival (G12C: HR = 0.72, p = 0.16, non-G12C: HR = 0.56, p = 0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest progression-free survival and overall survival (33.7 and 65.3 mo), which correlated with high tumor-infiltrating lymphocyte densities in the TME and up-regulation of interferon gamma target genes. Proinflammatory pathways according to TP53 status (mut versus wt) were less enhanced and not different in non-G12C and KRASwt, respectively., Conclusions: G12C/TP53 comutations identify a subset of patients with a very favorable long-term survival with immune checkpoint inhibitor monotherapy, mediated by highly active interferon gamma signaling in a proinflammatory TME., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Neuregulin 1 ( NRG1 ) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block ® ' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of "trial-ineligible" and "potentially trial-eligible" patients., Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either "potentially trial-eligible" or "trial-ineligible" according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042)., Results: Of 746 patients included, 343 patients (46.0%) were classified as "trial-ineligible" and had significantly worse outcomes compared with "potentially trial-eligible" patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2-8.4) versus 10.3 (95% CI: 8.4-13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19-1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4-20.3) versus 25.3 (95% CI: 19.8-30.4) months, hazard ratio of 1.36 (95% CI: 1.10-1.67), p equals 0.004., Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses., Competing Interests: Dr. Griesinger has received support for the present manuscript (grants to the institution) from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Furthermore, he has received grants (to the institution) from Amgen and Siemens; personal fees for consulting from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; and personal fees for participation on a data safety monitoring board or advisory board from Merck Sharp & Dohme. He declares an unpaid fiduciary role in the German Society of Hematology and Oncology (first author of Oncopedia recommendations) and in the German Cancer Society (S3 guidelines author). Dr. Sebastian has a consulting or advisory role and has received honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Eli Lilly, Merck Sharp & Dohme, Merck-Serono, Novartis, Pfizer, Roche, Takeda, and Tesaro; he has also received research funding from AstraZeneca. Dr. Brueckl has received personal fees and fees for lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche and fees for educational events from AstraZeneca, Boehringer, Eli Lilly, Pfizer, and Roche. Furthermore, he has received congress fees and personal fees from AstraZeneca, Boehringer, and Roche Pharma and has received personal fees and support for participation on advisory boards from AstraZeneca, Boehringer, Bristol-Myers Squibb, Eli Lilly Pharma, Novartis, Merck Sharp & Dohme and Roche. He declares a patent planned (EP21183549). Dr. Hummel has received personal fees as steering board member and fees for consulting from Amgen; has received personal fees for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Bristol-Myers Squibb, and Boehringer Ingelheim; payment for expert testimony from Amgen and Boehringer Ingelheim; support for attending meetings and/or travel from Amgen and Bristol-Myers Squibb; and personal fees for participation on a data safety monitoring board or advisory board from Amgen and Boehringer Ingelheim. Dr. Kern has received support for attending meetings and/or travel from AstraZeneca, Merck Sharp & Dohme, Pfizer, and Roche and for participation on advisory boards from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck/Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Dr. Wesseler has received honoraria for lectures and travel from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda. Dr. Hipper and Mrs. Groth have received research funding (to their employer AIO-Studien-gGmbH) from Amgen Ltd., AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, GlaxoSmithKline Research & Development Limited, Janssen-Cilag GmbH, Eli Lilly Deutschland GmbH, Merck Sharp & Dohme GmbH, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, and Takeda Pharma Vertriebs GmbH & Co. KG. Dr. Weichert has received research support (to the institution) from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; fees for consulting, travel support, fees for participation on advisory boards and lectures, and payment or honoraria for presentations, speakers bureaus, manuscript writing, or educational events from ADC, Agilent, Amgen, Astellas, AstraZeneca, Bayer, Boehringer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Illumina, Janssen, Eli Lilly, Merck, Molecular Health, Merck Sharp & Dohme, Novartis, Pfizer, Siemens, Takeda, and Roche. Mr. Dörfel holds iOMEDICO shares. Dr. Schröder has received consulting fees from iOMEDICO, Celgene, Roche, Bristol-Myers Squibb, Clovis Oncology GmbH, GlaxoSmithKline, Boehringer Ingelheim, Amgen, Novartis, Merck Sharp & Dohme, AOP, Searchlight, Pharma Partner, Medixline GmbH, Eisai, HE Research GmbH, AbbVie, NIO, I+E Research, Octapharma and IPSEN. Further he declares honoraria from iOMEDICO, Celgene, Roche, Bristol-Myers Squibb, Clovis Oncology GmbH, GlaxoSmithKline, Boehringer Ingelheim, Amgen, Novartis, Merck Sharp & Dohme, AOP, Searchlight, Pharma Partner, Medixline GmbH, Eisai, HE Research GmbH, AbbVie, NIO, I+E Research, Octapharma, IPSEN, BeiGene, and Miltenyi. Dr. Eberhardt has received research funding (to the institution) from Eli Lilly, AstraZeneca, and Bristol-Myers Squibb; honoraria for advisory boards from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Janssen-Cilag, Merck/Merck Sharp & Dohme, Roche, Pfizer, Novartis, Takeda, Boehringer Ingelheim, and AbbVie; and honoraria for lectures from Amgen, Baumgart Consult, Bristol-Myers Squibb, Merck/Merck Sharp & Dohme, Roche, Pfizer, Novartis, Takeda, Boehringer Ingelheim, and AbbVie. Dr. Thomas has received research funding (to the institution) from AstraZeneca, Bristol-Myers Squibb, Merck, Roche, and Takeda; personal fees for speakers bureaus and advisory boards from Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda; and support for attending meetings and/or travel from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda. The remaining authors declare no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

Introduction: SARS-CoV-2 infected patients with cancer have a worse outcome including a significant higher mortality, compared to non-cancer patients. However, limited data are available regarding in-hospital mortality during the Omicron phase of the pandemic. Therefore, the aim of the study was the comparison of mortality in patients with history of cancer and patients with active cancer disease during the different phases of the COVID-19 pandemic, focusing on the current Omicron variant of concern., Methods: We conducted a multicenter, observational, epidemiological cohort study at 45 hospitals in Germany. Until July 20, 2022, all adult hospitalized SARS-CoV-2 positive patients were included. The primary endpoint was in-hospital mortality regarding cancer status (history of cancer and active cancer disease) and SARS-CoV-2 virus type., Results: From March 11, 2020, to July 20, 2022, a total of 27,490 adult SARS-CoV-2 positive patients were included in the study. 2,578 patients (9.4%) had diagnosis of cancer, of whom 1,065 (41.3%) had history of cancer, whereas 1,513 (58.7%) had active cancer disease. Overall 3,749 out of the total of 27,490 patients (13.6%) died during the hospital stay. Patients with active cancer disease had a significantly higher mortality compared to patients without cancer diagnosis, in both phases of the pandemic (wild-type to Delta: OR 1.940 [1.646-2.285]); Omicron: 2.864 [2.354-3.486]). After adjustment to co-variables, SARS-CoV-2 infected patients with active cancer disease had the highest risk for in-hospital mortality compared to the other groups, in both phases of the pandemic., Conclusion: The CORONA Germany study indicates that hospitalized patients with active cancer disease are at high risk of death during a SARS-CoV-2 infection. Mortality of patients with history of cancer improved to nearly the level of non-cancer patients during Omicron phase., (© 2023 S. Karger AG, Basel.)

Background: Dementia has been identified as a major predictor of mortality associated with COVID-19., Objective: The objective of this study was to investigate the association between dementia and mortality in COVID-19 inpatients in Germany across a longer interval during the pandemic., Methods: This retrospective study was based on anonymized data from 50 hospitals in Germany and included patients with a confirmed COVID-19 diagnosis hospitalized between March 11, 2020 and July, 20, 2022. The main outcome of the study was the association of mortality during inpatient stays with dementia diagnosis, which was studied using multivariable logistic regression adjusted for age, sex, and comorbidities as well as univariate logistic regression for matched pairs., Results: Of 28,311 patients diagnosed with COVID-19, 11.3% had a diagnosis of dementia. Prior to matching, 26.5% of dementia patients and 11.5% of non-dementia patients died; the difference decreased to 26.5% of dementia versus 21.7% of non-dementia patients within the matched pairs (n = 3,317). This corresponded to an increase in the risk of death associated with dementia (OR = 1.33; 95% CI: 1.16-1.46) in the univariate regression conducted for matched pairs., Conclusion: Although dementia was associated with COVID-19 mortality, the association was weaker than in previously published studies. Further studies are needed to better understand whether and how pre-existing neuropsychiatric conditions such as dementia may impact the course and outcome of COVID-19.

Objectives: For refractory NSCLC patients with EGFR mutations, recent studies have demonstrated a favorable response to the combination of anti-angiogenic therapy and checkpoint inhibition but included only very few patients with uncommon EGFR mutations for which treatment options are still limited despite new targeted treatments., Materials and Methods: Sixteen stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers were treated in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV., Results: Patients with either an Exon 20 insertion (n = 9) or other uncommon EGFR mutations (n = 7) received ABCP in first, second or further line. Nine patients had received a TKI therapy in first line with an ORR of 66.7 % and a median time-to-next-treatment of 6.7 months. After a median number of 4 ABCP cycles, 4 patients (25.0 %) required a dose reduction of chemotherapy and 5 patients (31.3 %) suffered from grade 3 or 4 toxicity. Overall response rate was 81.3 % and disease control rate 87.5 %. 14 patients (87.5 %) received a maintenance with AB and the median follow-up after initial diagnosis was 24.3 months. Median PFS was 13.6 months for both the entire cohort and for Exon 20 insertions. Corresponding median OS was either not reached or 30.7 months. Landmark analysis at 12 months gave a PFS of 42.8 % and an OS of 93.3 %. Four patients were rechallenged with ABCP while progressing under maintenance and responded again. In further line therapy, clinical benefit was achieved in all of 3 patients receiving Amivantamab, but in only one of four patients receiving mobocertinib., Conclusion: In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations and is a valuable option in the early treatment course., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AT, ND, ID, PH, TO, CW and MR have received honoraria or travel expenses from Roche/Genentech. MR is part of the Speakers Bureau of Roche/Genentech., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce., Patients and Methods: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases., Results: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8 + and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants., Conclusions: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival., Competing Interests: Conflict of interest statement PC: research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Takeda. JR: lecture fees from AstraZeneca, Boehringer Ingelheim. FCS: research funding from Roche; non-financial support from Lilly; personal fees from Takeda, and Pfizer, outside the submitted work. BH: advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche, Pfizer. JK: research funding from AstraZeneca and Celgene. MJ: speaker's honoraria from Roche, Boehringer, and travel grants from Daiichi Sankyo. DK: advisory boards/speakers honoraria from AstraZeneca, BMS, Boehringer Ingelheim, GSK, MSD, Novartis, Pfizer, Roche, Takeda. FE: speaker's honoraria from Roche. FB: research funding from AstraZeneca, BMS and Roche, and travel grants from BMS and MSD. RS: research funding from BMS, and speaker's honoraria from AstraZeneca and Roche. AT: research funding from BMS. MW: research funding from Roche; Personal fees from Roche, AstraZeneca, Boehringer, Kite, Novartis, Merck, BMS, Heidelberg Pharma; Non-financial support from AstraZeneca, BMS, Glenmark; outside the submitted work. SL: advisory board, speaker's honoraria and travel support from BerGenBio, Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AstraZeneca, Sanofi, as well as research funding from Roche, BMS, BerGenBio. WB: consulting fees from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Sanofi, honoraria for lectures from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Sanofi. Travel grants from AstraZeneca, Boehringer Ingelheim, MSD, Roche. CS: advisory board honoraria from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Novartis, Roche, Pfizer, Takeda. Speaker's honoraria from AstraZeneca, Boehringer, Lilly, Roche, MSD, Takeda. DM: advisory board/lecture fees from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi and Takeda (no personal honoraria) NF: advisory board/lecture fees from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, Roche, MSD, Takeda. JK: advisory board member without receiving any personal fees for Roche Pharma, Boehringer Ingelheim, BMS, MSD, Amgen, Lilly and Takeda. MR: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung. FG: grants and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Takeda, as well as personal fees from AbbVie, Tesaro/GSK, Blueprint Medicines, Amgen. CG: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Takeda, MSD, Novartis, Pfizer, Roche, AbbVie, Tesaro/GSK and Blueprints Medicines. AS: advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker's honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai and BMS. MT: advisory board honoraria from Novartis, Eli Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer Ingelheim, Pfizer, speaker's honoraria from Eli Lilly, MSD, Takeda, Pfizer, research funding from AstraZeneca, BMS, Celgene, Novartis, Roche, Takeda, and travel grants from BMS, MSD, Novartis, Boehringer. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Immune related endonucleases have recently been described as potential therapeutic targets and predictors of response to treatment with immune checkpoint inhibitors (ICI). The aim is to evaluate the association between the expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d and Cytohesin-3) in parallel with the more common ICI-predictive markers, PD-L1 expression and Tumor Mutation Burden (TMB) with response to ICI therapy in an advanced non-small cell lung cancer (NSCLC) cohort., Methods: Patients with advanced NSCLC treated with ICI single agent were divided into responders and non-responders according to RECIST v1.1 and duration of response (DOR) criteria. Immunohistochemistry was performed on pretreatment tumor tissue samples for PD-L1, CD73, CD39, VISTA, Arl4d, and Cytohesin-3 expression. TMB was estimated with NEOplus v2 RUO (NEO New Oncology GmbH) hybrid capture next generation sequencing assay. Resistance mutations in STK11/KEAP1 and positive predictive mutations in ARID1A/POLE were also evaluated., Results: Included were 56 patients who were treated with ICI single agent. The median progression-free and overall survival for the whole cohort was 3.0 (95% CI, 2.4-3.6) and 15 (95% CI, 9.7-20.2) months, respectively. The distribution of CD73 in tumor cells and CD39, VISTA, Arl4d and Cytohesin-3 expression in immune cells were not different between responders and non-responders. Also, PD-L1 and TMB were not predictive for response. The frequency of STK11, KEAP1 and ARID1A mutations was low and only observed in the non-responder group., Conclusion: Separate and combined expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d, and Cytohesin-3) was not associated with response in our cohort of advanced NSCLC patients receiving single agent ICI. To confirm our findings the analysis of independent larger cohorts is warranted., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Acute myocardial injury (AMJ), assessed by elevated levels of cardiac troponin, is associated with fatal outcome in coronavirus disease 2019 (COVID-19). However, the role of acute cardiovascular (CV) events defined by clinical manifestation rather than sole elevations of biomarkers is unclear in hospitalized COVID-19 patients., Objective: The aim of this study was to investigate acute clinically manifest CV events in hospitalized COVID-19 patients., Methods: From 1 March 2020 to 5 January 2021, we conducted a multicenter, prospective, epidemiological cohort study at six hospitals from Hamburg, Germany (a portion of the state-wide 45-center CORONA Germany cohort study) enrolling all hospitalized COVID-19 patients. Primary endpoint was occurrence of a clinically manifest CV-event., Results: In total, 132 CV-events occurred in 92 of 414 (22.2%) patients in the Hamburg-cohort: cardiogenic shock in 10 (2.4%), cardiopulmonary resuscitation in 12 (2.9%), acute coronary syndrome in 11 (2.7%), de-novo arrhythmia in 31 (7.5%), acute heart-failure in 43 (10.3%), myocarditis in 2 (0.5%), pulmonary-embolism in 11 (2.7%), thrombosis in 9 (2.2%) and stroke in 3 (0.7%). In the Hamburg-cohort, mortality was 46% (42/92) for patients with a CV-event and 33% (27/83) for patients with only AMJ without CV-event (OR 1.7, CI: (0.94-3.2), p = 0.077). Mortality was higher in patients with CV-events (Odds ratio(OR): 4.8, 95%-confidence-interval(CI): [2.9-8]). Age (OR 1.1, CI: (0.66-1.86)), atrial fibrillation (AF) on baseline-ECG (OR 3.4, CI: (1.74-6.8)), systolic blood-pressure (OR 0.7, CI: (0.53-0.96)), potassium (OR 1.3, CI: (0.99-1.73)) and C-reactive-protein (1.4, CI (1.04-1.76)) were associated with CV-events., Conclusion: Hospitalized COVID-19 patients with clinical manifestation of acute cardiovascular events show an almost five-fold increased mortality. In this regard, the emergence of arrhythmias is a major determinant.

Background: Chemotherapy plus immune-checkpoint inhibitor (CTx+ICI) therapy has become the preferred 1st line treatment in patients with metastatic NSCLC without oncogenic driven mutations. However, the optimal subsequent 2nd line treatment is not defined and several alternatives exist. The purpose of this analysis was to evaluate the efficacy of 2nd line docetaxel plus ramucirumab (D+R) initiated after failure of 1st line CTx+ICI., Methods: Retrospective data were collected during routine care from German thoracic oncology centers. Only patients who had received at least one course of 2nd line D+R were included. ORR, PFS, OS and numbers of courses of D+R were investigated with PFS after initiation of D+R being the primary endpoint., Results: Seventy-seven patients met the inclusion criteria. 2nd line treatment with D+R achieved an ORR and DCR of 32.5% and 62.4%, respectively. Median PFS for 2nd line therapy was 3.9 months with a DOR of 6.4 months. Median OS of 15.5 and 7.5 months were observed from the start of 1st line therapy and 2nd line treatment, respectively. No unexpected toxicities occurred. Presence of KRAS mutations was associated with significantly worse median PFS to D+R (2.8 vs. 4.5 months in wild-type cases; P=0.021) and was an independent predictor of inferior PFS in multivariate analysis., Conclusions: D+R is an effective and safe 2nd line treatment after failure of 1st line CTx+ICI irrespective of NSCLC histology. However, patients with a KRAS mutation did not benefit from D+R in terms of PFS and will require further investigations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-197). Albrecht Stenzinger serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. The following authors received honoraria for lectures, presentation, speakers bureaus, manuscript writing or educational events: WMB from AstraZeneca, Boehringer, Novartis, MSD, BMS, Roche and Lilly; MR from Amgen, AstraZeneca, BMS, Boehringer, Lilly, Minde, Merck, MSD, Novartis, Pfizer and Roche; AR from AbbVIe, AstraZeneca, BMS, Boehringer, Lilly, MSD, Novartis, Pfizer and Roche; CW from Boehringer, Lilly, MSD, Roche, AstraZeneca, BMS, Sanofi Aventis and Takeda; GHW from Boehringer, Lilly, MSD, Roche, AstraZeneca, BMS, Sanofi Aventis, Takeda, Glaxo and Berlin Chemie; PC from Roche, Takeda, AstraZeneca and Novartis; AS from Aignostics, Bayer, Thermo Fisher, Illumina, AstraZeneca, Novartis, Pfizer, Roche, Seattle Genetics, MSD, BMS, Takeda and Lilly; AT from GSK, Novartis, Amgen, BMS, MSD, Lilly, Pfizer, Boehringer, Roche, Takeda and Celgene; JHF from AstraZeneca, Boehringer, Novartis, MSD, BMS and Roche. The following authors received support for attending meetings and/or travel: WMB from Boehringer, AstraZeneca and Roche; CW from Boehringer, MSD, Roche, AstraZeneca and BMS; GW from Boehringer, MSD, Roche, AstraZeneca and Berlin Chemie; PC from AstraZeneca, Takeda, Novartis and Lilly; AT from GSK, Novartis, Amgen, MSD, BMS, Lilly, Pfizer, Boehringer, Roche, Takeda and Celgene; JHF from Boehringer and AstraZeneca. The following authors participated on a data safety monitoring board or an advisory board: WMB on AstraZeneca, Boehringer, Novartis, MSD, Lilly, BMS and Roche; JK on Roche, Boehringer, BMS, Merck, Amgen, Takeda and Lilly (all outside the submitted work and all without receiving any personal fees; CW on Boehringer, MSD, Roche, AstraZeneca and MBS; GHW on Boehringer, MSD, Roche, AstraZeneca and BMS; PC on Pfizer, Chugai, Boehringer and Roche; AT on GSK, Novartis, Amgen, MSD, BMS, Lilly, Pfizer, Boehringer, Roche, Takeda, Celgene and AIO Leadership Group; PH on Lilly, MSD, BMS, AstraZeneca, Takeda, Roche, Boehringer and Pfizer; JHF on AstraZenca. The following authors receipt equipment, materials, drugs, medical writing, gifts or other services: WMB from Boehringer (for medical writing); JHF from Novartis (for medical writing); the following authors received consulting fees: AR from AbbVie, AstraZeneca, BMS, Boehringer, Lilly, MSD, Novartis, Pfizer and Roche. The following authors received grants or contracts form any entity: PC from Roche, Takeda, AstraZeneca and Novartis (all research grants to the institution; AT from AstraZeneca (research grant). The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: After one year of the pandemic and hints of seasonal patterns, temporal variations of in-hospital mortality in COVID-19 are widely unknown. Additionally, heterogeneous data regarding clinical indicators predicting disease severity has been published. However, there is a need for a risk stratification model integrating the effects on disease severity and mortality to support clinical decision-making., Methods: We conducted a multicenter, observational, prospective, epidemiological cohort study at 45 hospitals in Germany. Until 1 January 2021, all hospitalized SARS CoV-2 positive patients were included. A comprehensive data set was collected in a cohort of seven hospitals. The primary objective was disease severity and prediction of mild, severe, and fatal cases. Ancillary analyses included a temporal analysis of all hospitalized COVID-19 patients for the entire year 2020., Findings: A total of 4704 COVID-19 patients were hospitalized with a mortality rate of 19% (890/4704). Rates of mortality, need for ventilation, pneumonia, and respiratory insufficiency showed temporal variations, whereas age had a strong influence on the course of mortality. In cohort conducting analyses, prognostic factors for fatal/severe disease were: age (odds ratio (OR) 1.704, CI:[1.221-2.377]), respiratory rate (OR 1.688, CI:[1.222-2.333]), lactate dehydrogenase (LDH) (OR 1.312, CI:[1.015-1.695]), C-reactive protein (CRP) (OR 2.132, CI:[1.533-2.965]), and creatinine values (OR 2.573, CI:[1.593-4.154]., Conclusions: Age, respiratory rate, LDH, CRP, and creatinine at baseline are associated with all cause death, and need for ventilation/ICU treatment in a nationwide series of COVID 19 hospitalized patients. Especially age plays an important prognostic role. In-hospital mortality showed temporal variation during the year 2020, influenced by age., Trial Registration Number: NCT04659187., Competing Interests: The authors have declared that no competing interests exist that could be perceived to bias this work. The commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. SW reports grants and personal fees from Abbott and personal feels from Abbott, Boston Scientific, Boehringer Ingelheim, Bristol Myers Squibb, Bayer Vital, Acutus, and Daiichi Sankyo, outside the submitted work.

Introduction: JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma ( KRAS ) mutation., Methods: JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety., Results: Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib., Conclusions: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02152631., (Copyright © 2020 Goldman, Mazieres, Barlesi, Dragnev, Koczywas, Göskel, Cortot, Girard, Wesseler, Bischoff, Nadal, Park, Lu, Taus, Cobo, Estrem, Wijayawardana, Turner, Oakley, Hurt, Chiang, Hossain, John and Paz-Ares.)

Background: Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects with chemotherapy. Effects might be even stronger after immune-checkpoint-inhibitor (ICI) therapy. The purpose of this analysis was to evaluate the efficacy of ramucirumab plus docetaxel (R + D) as third-line treatment after failure of a first-line platinum-based chemotherapy and a second-line ICI treatment in patients with non-small-cell lung cancer (NSCLC) stage IV., Methods: Retrospective data were collected from 9 German thoracic oncology centers. Only patients who had received at least 1 cycle of third-line R + D were included. The numbers of cycles, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated., Results: Sixty-seven patients met the criteria for inclusion. Third-line treatment with R + D achieved an ORR of 36% and a disease control rate (DCR) of 69%. Median PFS for third-line therapy was 6.8 months with a duration of response (DOR) of 10.2 months. A median OS of 29 months was observed from the start of first-line therapy with a median OS of 11.0 months from the start of third-line treatment. No unexpected toxicities occurred., Conclusion: R + D is a highly effective and safe third-line treatment after failure of second-line programmed cell death protein 1/programmed cell death-ligand 1 (PD1/PD-L1)-derived ICI therapy irrespective of NSCLC histology. As there may be synergistic effects of second- and third-line treatments, this sequence is a very suitable option for patients not treated with first-line ICI. In addition, R + D should continue to be investigated as a second-line treatment option after failure of chemotherapy plus ICI in the palliative first-line treatment., Competing Interests: Declaration of Conflicting Interest:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: W.M.B. and J.H.F. have received honoraria for consulting from Astra Zeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, MSD, Pfizer, and Roche Pharma. P.C. reports consulting honoraria from Astra Zeneca, Boehringer Ingelheim, Chugai, Lilly, Novartis, Pfizer, Roche, and Takeda. P.H. has received honoraria for consulting from Boehringer Ingelheim, Pfizer, Takeda, Roche Pharma, Lilly, BMS, MSD, AstraZeneca, and Abbvie. F.R. has received honoraria for consulting from Astra Zeneca, Chugai Pharma, and Roche Pharma. C.W. and G.H.W. have received honoraria for consulting from Astra Zeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Pfizer, and Roche Pharma. The other authors reported no conflict of interest., (© The Author(s) 2020.)

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved "precision" drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC.