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Introduction Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRASG12C variant has recently become targetable by a new drug class specifically locking KRASG12C in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRASG12C mutations but was limited by the development of resistance. Methods A biopsy from progressing lung cancer of a patient treated with the KRASG12C inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRASG12C inhibition. Results We demonstrated acquisition of HER2 copy number gain and KRASG12C mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRASG12C lung cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRASG12C inhibitor treatment. Combined pharmacological inhibition of KRASG12C and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo. Conclusions These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRASG12C inhibition that can be overcome by co-targeting SHP2.

Introduction: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7, including premenopausal and postmenopausal patients without pretreatment as well as patients with up to 3 previous treatment lines for advanced disease. Here we present the final analysis for the primary endpoint. Methods:The study enrolled women or men with metastatic or locally advanced breast cancer irrespective of their menopausal status, who were not amenable to curative treatment by surgery or radiotherapy. Histological or cytological confirmation of HR+, HER2- breast cancer was required. 502 patients were enrolled in two Cohorts. Cohort A (n=319): postmenopausal women and men without pretreatment for advanced disease; Cohort B (n=183): premenopausal women without pretreatment for advanced disease and pre- or postmenopausal women and men with ≤ 1 line of chemotherapy and/or ≤ 2 lines of endocrine therapy in the advanced situation. The primary endpoint was to assess the clinical benefit rate (CBR, defined as CR, PR or SD, or NCRNPD) at 24 weeks for the overall study population. Secondary endpoints included: progression free survival (PFS), overall survival (OS), safety, and changes in quality of life as assessed by EORTC QLQ-C30 and -BR23 questionnaires. Results: The study ended 84 weeks after the enrollment of the last patient. The median observation time was 10.6 months (0.1-38 months). Baseline characteristics: of 502 pts, 5 were male, 497 were female(46 pre-or perimenopausal, 451 postmenopausal); median age: 64 yrs; ECOG 0-1: 96.8%; 71.1 % of pts had bone metastases (40.8% bone only), 30.6% liver, 27.5% lung and 30.1% other metastases. 97.3% had at least 1 metastatic site: 48.7% had 1, 35.1% had 2, 12.9% had 3 and 1.6% had 4 metastatic sites, respectively. 78.9% received at least one prior antineoplastic therapy: 4.9% received neoadjuvant, 56.8% adjuvant and 37.8% palliative treatment as last antineoplastic therapy before study start. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (60.6%), nausea (42%), fatigue (39.2%), alopecia (35.1%), leukopenia or WBC decreased (30.7%), nasopharyngitis (28.5%), diarrhea (25.3%), ALT increased (22.9%) and AST increased (20.7%). The CBR at week 24 for the overall study population was 69.2%. Median PFS was 16.5 [95%CI 13.7; 19.3] months in the overall study population, 21.8 [15.4; 25.3] months and 9.3 [8.1; 16.3] months in Cohort A and B, respectively. At 72 weeks, the Kaplan-Meier estimate for OS was 86.8% [83.3; 89.6]. Because of the low number of events during the study period, median OS could not be determined. Conclusion: The results of the final analysis confirmed clinical benefit of ribociclib and letrozole in this patient population. No new safety signals emerged. Citation Format: Mattea Reinisch, Arndt Nusch, Thomas Decker, Andreas Hartkopf, Bernhard J Heinrich, Christian M Kurbacher, Roswitha Fuchs, Hans Tesch, Petra Krabisch, Sara Y Brucker, Tanja Fehm, Wolfgang Janni, Sherko Kuemmel, Diana Lüftner, Andreas Schneeweiss, Martin Schuler, Claudia Voges, Joerg Schubert, Peter A Fasching. Ribecca - a phase 3b, multi-center, open label study for women with estrogen receptor positive, locally advanced or metastatic breast cancer treated with ribociclib (lee011) in combination with letrozole: Final results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-31.

Purpose/introduction [18F]FDG-PET/CT is the standard imaging-technique for radiation treatment (RT) planning in locally advanced non-small cell lung cancer (NSCLC). The purpose of this study was to examine the additional value of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) to standard PET/CT for mediastinal lymph-node (LN) staging and its impact on clinical target volume (CTV). Materials and methods All consecutive patients with primary stage III NSCLC who underwent [18F]FDG-PET/CT and EBUS-TBNA prior to RT were analyzed from 12/2011 to 06/2018. LN-stations were assessed by an expert-radiologist and a nuclear medicine-physician. CTV was evaluated by two independent radiation oncologists. LNs were grouped with increasing distance along the lymphatic chains from primary tumor into echelon-1 (ipsilateral hilum), echelon-2 (LN-station 7 and ipsilateral 4), and echelon-3 (remaining mediastinum and contralateral hilum). Results A total of 675 LN-stations of which 291 were positive for tumor-cells, were sampled by EBUS-TBNA in 180 patients. The rate of EBUS-positive LNs was 43% among all sampled LNs. EBUS-positivity in EBUS-probed LNs decreased from 85.8% in echelon-1 LNs to 42.4%/ 9.6% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher’s exact test). The false discovery rate of PET in comparison with EBUS results rose from 5.3% in echelon-1 to 32.9%/ 69.1% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher’s exact test). Sensitivity and specificity of FDG-PET/CT ranged from 85 to 99% and 67 to 80% for the different echelons. In 22.2% patients, EBUS-TBNA finding triggered changes of the treated CTV, compared with contouring algorithms based on FDG-avidity as the sole criterion for inclusion. CTV was enlarged in 6.7% patients due to EBUS-positivity in PET-negative LN-station and reduced in 15.5% by exclusion of an EBUS-negative but PET-positive LN-station. Conclusion The false discovery rate of [18F]FDG-PET/CT increased markedly with distance from the primary tumor. Inclusion of systematic mediastinal LN mapping by EBUS-TBNA in addition to PET/CT has the potential to increase accuracy of target volume definition, particularly in echelon-3 LNs. EBUS-TBNA is recommended as integral part of staging for radiochemotherapy in stage III NSCLC.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial–mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.

Introduction: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7. Here we present the results of the third preplanned interim analysis. Methods: Main inclusion criteria allowed enrollment of men or women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of HR+, HER2- breast cancer, irrespective of their menopausal status. The primary objective is to assess the clinical benefit rate (CBR) after 6 months. Secondary objectives include: progression free survival (PFS), overall survival (OS), safety and changes in quality of life. Here we describe a preliminary analysis baseline characteristics, safety data and the clinical benefit rate (CBR) at 24 weeks, of all enrolled patients (n=502). Results: The cut-off date for this third interim analysis was 6 months after the last patient was enrolled in the study. The median observation time for all patients in this analysis was 9.4 months (0.1-26.0 months). Baseline characteristics: of 502 pts, 497 were female and 5 male. Median age: 64 yrs; 46 pts pre-or perimenopausal, 451 postmenopausal (missing: 5); ECOG 0-1: 96.8%; median time since first recurrence: 1.6 months; 71.1 % of pts had bone metastases (40.8% bone only), 30.1% liver, 28.1% lung and 30.1% other metastases. Median relative dose intensity was 0.90 for ribociclib and 1 for letrozole. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (57.8%), nausea (41.2%), fatigue (37.5%), alopecia (34.5%), leukopenia or WBC decreased (29.7%), nasopharyngitis (24.7%), diarrhea (23.5%), ALT increased (21.5%) and AST increased (19.7%). The CBR by week 24 was 69.2%. Conclusion: The results of the third interim analysis confirmed clinical benefit in this patient population. No new safety signals were detected. This is in line with data published from the pivotal phase III studies MONALEESA-2, MONALEESA-3 and MONALEESA-7. Citation Format: Andreas Hartkopf, Arnd Nusch, Thomas Decker, Mattea Reinisch, Bernhard J Heinrich, Christian Kurbacher, Roswitha Fuchs, Hans Tesch, Petra Krabisch, Sara Brucker, Tanja N Fehm, Wolfgang Janni, Sherko Kümmel, Diana Lüftner, Andreas Schneeweiss, Martin H Schuler, Claudia Voges, Jörg Schubert, Peter A Fasching. RIBECCA - A phase IIIb, multi-center, open label study for women with estrogen receptor positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole: Results of the third interim analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-31.

Mutació del MET; Capmatinib Mutación del MET; Capmatinib MET mutation; Capmatinib Background Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). Conclusions MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479). This study was funded by Novartis Pharmaceuticals Corporation.

Objectives MET c-Cbl binding site mutations constitute about 2 % of MET exon 14 alterations in lung cancer. Preclinical data suggests regarding these mutations as functional analogs of MET exon 14 skipping mutations, but clinical validation is lacking. Results We report the case of a patient with metastastic lung adenocarcinoma harboring a c-Cbl binding site alteration and demonstrate clinical, radiological and metabolic response to crizotinib with a PFS of 10.6 months. As escape mechanism, a typical MET resistance mutation could be identified. Conclusion MET c-Cbl binding site mutations should be regarded as a distinct subtype of MET exon 14 alterations. Patients with lung cancer harboring such mutations should be offered targeted therapy.

Highlights • High concordance rate in variant calls from tumor biopsies and the corresponding liquid biopsy-derived DNA sample. • ctDNA sequencing allows for unbiased characterization of molecular tumor architecture and reveal the presence of otherwise undetectable resistance-mediating tumor cell clones. • Serial ctDNA analysis allows for monitoring tumor dynamics but limited by tumor cell clonal molecular heterogeneity. • cfDNA methylation analysis using methylation-sensitive restriction enzyme-coupled ddPCR can complement cfDNA mutation scoring to broaden the spectrum of eligible patients for molecular surveillance., Background Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility. Methods We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays. Results A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (methcfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in methcfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status. Conclusion Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring

BackgroundGrowth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. Recent research has though indicated a prominant role in modulation of the tumor microenvironment and the immune synapse, too1 2 indicating that GDF-15 may be a major tumor-derived immunosuppressant. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15.MethodsThis is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments, including prior anti-PD1/-PD-L1 treatment, and present with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for ”GDF-15 Antibody-mediaTed Effector cell Relocation”.Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect)In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a ”mono-followed-by-combination”-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination.The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 4 is ongoing at time of submission (07/2021) and so far no DLT has occurred. Updated safety, biomarker and response assessments will be reported at the meeting. The ClinicalTrials.gov Identifier is NCT04725474. For more information please contact info@catalym.com.Trial RegistrationNCT04725474ReferencesWischhusen J, Wistuba-Hamprecht K, Harter PN, Cheng P, Martens A, Gogolla F, Nonomura Y, Romer P, Koch SD, Haake M, Schuberth-Wagner C, Rudiger M, Leo E, Mittelbronn M, Levesque MP, Hackl H, Dummer R, Weide B. Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27–28 and Jun 22–24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl): Abstract nr 2161.Hurt E, Thomas S, Mulgrew K, Blackmore S, Moynihan J, Cusdin F, Dodd R, Cariuk P, Sigurdardottir A, Brannigan E, Dobson C, Kumar R, Cobbold M. AZD8853: A novel antibody targeting GDF15 for immunotherapy refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10–15 and May 17–21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl): Abstract nr 1828.Ethics ApprovalAll participants gave informed consent prior to participation. EC approval by Gobierno de Navarra, Departamento de Salud, EC_2020/30, Dated: Oct 13, 2020 in Pamplona, Spain. Respective additional national lead EC approvals for Germany (Ethikkommission der Universität Würzburg, 203–20ff of Oct 26, 2020) and Switzerland (Kantonale Ethikkommission Zürich, 2020–02308 of Nov 24, 2020).

Background Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare entity occurring in less than 4% of all lung cancers. Due to its low differentiation and high glucose transporter 1 (GLUT1) expression, LCNEC demonstrates an increased glucose turnover. Thus, PET/CT with 2-[18F]-fluoro-deoxyglucose ([18F]FDG) is suitable for LCNEC staging. Surgery with curative intent is the treatment of choice in early stage LCNEC. Prerequisite for this is correct lymph node staging. This study aimed at evaluating the diagnostic performance of [18F]FDG PET/CT validated by histopathology following surgical resection or mediastinoscopy. N-staging interrater-reliability was assessed to test for robustness of the [18F]FDG PET/CT findings. Methods Between 03/2014 and 12/2020, 46 patients with LCNEC were included in this single center retrospective analysis. All underwent [18F]FDG PET/CT for pre-operative staging and subsequently either surgery (n = 38) or mediastinoscopy (n = 8). Regarding the lymph node involvement, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for [18F]FDG PET/CT using the final histopathological N-staging (pN0 to pN3) as reference. Results Per patient 14 ± 7 (range 4–32) lymph nodes were resected and histologically processed. 31/46 patients had no LCNEC spread into the lymph nodes. In 8/46 patients, the final stage was pN1, in 5/46 pN2 and in 2/46 pN3. [18F]FDG PET/CT diagnosed lymph node metastasis of LCNEC with a sensitivity of 93%, a specificity of 87%, an accuracy of 89%, a PPV of 78% and a NPV of 96%. In the four false positive cases, the [18F]FDG uptake of the lymph nodes was 33 to 67% less in comparison with that of the respective LCNEC primary. Interrater-reliability was high with a strong level of agreement (κ = 0.82). Conclusions In LCNEC N-staging with [18F]FDG PET/CT demonstrates both high sensitivity and specificity, an excellent NPV but a slightly reduced PPV. Accordingly, preoperative invasive mediastinal staging may be omitted in cases with cN0 disease by [18F]FDG PET/CT. In [18F]FDG PET/CT cN1-cN3 stages histological confirmation is warranted, particularly in case of only moderate [18F]FDG uptake as compared to the LCNEC primary.

Current therapy of advanced cancers is based on several modalities including radiotherapy, cytotoxic chemotherapy, molecularly targeted inhibitors and antibodies targeting immune checkpoints. All of those these modalities can negatively impact the cardiovascular system, and there is considerable experience in relation to radiotherapy and chemotherapy. In contrast, the knowledge base on cardiovascular toxicities of novel agents targeting signal transduction pathways and immune regulation is quite limited. In particular, potential late effects are of concern as cardiovascular pathology can negatively impact quality of life and prognosis in cancer survivors, particularly when additional cardiovascular risk factors are present. Treatment-associated adverse events include hypertension, venous thromboembolism, coronary artery disease, valvular heart disease, heart failure and arrhythmias. Early diagnosis of subclinical cardiotoxic effects of cancer therapies remains challenging. Integrated care, as provided by multidisciplinary cardio-oncology teams is the best option for prevention, diagnosis and treatment of cardiovascular diseases associated with cancer therapy. This review considers the cardiotoxic effects of specific cancer therapies and discusses novel diagnostic and therapeutic approaches as a reference for optimizing the care of cancer patients receiving novel cancer therapies.

The German Cancer Consortium (‘Deutsches Konsortium für Translationale Krebsforschung’, DKTK) is a long-term cancer consortium, bringing together the German Cancer Research Center (DKFZ), Germany's largest life science research center, and the leading University Medical Center-based Comprehensive Cancer Centers (CCCs) at seven sites across Germany. DKTK was founded in 2012 following international peer review and has positioned itself since then as the leading network for translational cancer research in Germany. DKTK is long term funded by the German Ministry of Research and Education and the federal states of each DKTK partner site. DKTK acts at the interface between basic and clinical cancer research, one major focus being to generate suitable multisite cooperation structures and provide the basis for including higher numbers of patients and facilitate effective collaborative forward and reverse translational cancer research. The consortium addresses areas of high scientific and medical relevance and develops critical infrastructures, for example, for omics technologies, clinical and research big data exchange and analysis, imaging, and clinical grade drug manufacturing. Moreover, DKTK provides a very attractive environment for interdisciplinary and interinstitutional training and career development for clinician and medical scientists. CA extern

Background With improvement of cancer-specific survival, comorbidities and treatment-related side effects, particularly cardiovascular toxicities, need close attention. The aim of the present study was to evaluate clinical characteristics and outcomes of cancer patients requiring coronary angiography during inpatient care. Methods We performed a retrospective analysis of patients hospitalized between 02/2011 and 02/2018 in our two university hospital cancer centers. From a cohort of 60,676 cancer patients, we identified 153 patients (65.7 ± 11.6 years, 73.2% male), who underwent coronary angiography and were eligible for analysis. These were compared to a control group of 153 non-cancer patients pair-matched with respect to age, sex, and indication for catheterization. Results Cancer patients presented in 66% with an acute coronary syndrome (ACS). The most prevalent cancer entities were lymphoma (19%) and lung cancer (18.3%). The rate of primary percutaneous coronary interventions (PCI) was significantly lower in the cancer cohort (40.5% vs. 53.6%, p = 0.029), although manifestation of coronary artery disease (CAD) and PCI results were comparable (SYNergy between PCI with TAXus and cardiac surgery (SYNTAX)-score, delta pre- and post-PCI − 9.8 vs. − 8.0, p = 0.2). Mortality was remarkably high in cancer patients (1-year mortality 46% vs. 8% in non-cancer patients, p Conclusion Strategies to effectively control cardiovascular risks in cancer patients are needed. Additionally, suspected CAD in cancer patients should not prevent prompt diagnostic clarification and optimal revascularization as PCI results in cancer patients are comparable to non-cancer patients and occurrence of troponin-positive ACS leads to a significantly increased risk of mortality. Graphic Abstract

Objective BRAF mutations have been subtyped in three functional classes with different oncogenic modes of action. The clinical impact of BRAF mutational subtypes in non–small-cell lung cancer (NSCLC) remains to be defined. So far, ambiguous results were reported from analyses of heterogeneous patient cohorts. Methods We studied patients with metastatic or recurrent NSCLC who were sequentially enrolled in precision oncology programs at two large German lung cancer centres from 2009 to 2019. The study period allowed evaluating the specific impact of BRAF V600E-targeting. Results In a cohort of 72 patients, BRAF mutation subtyping revealed p.V600E mutations in 31 cases (43%), whereas 41 cases (57%) harboured 18 different BRAF mutational subtypes of functional classes II/III. Functionally relevant comutations were observed in 6.4% of class I, and 24.4% of class II/III BRAF mutations. Most patients were treated with chemotherapy. Targeted therapy was administered in 11 patients with a response rate of 72.7%. PD-1/PD-L1-immunotherapy was given in 14 patients with a response rate of 28.6%. Overall survival of patients with BRAF-mutated NSCLC was inferior (HR 1.38, p = 0.048) as compared to patients with BRAF wild-type cancers. Median time-to-treatment-failure with BRAF-targeting agents was shorter as compared to approved targeted therapy of other oncogenic drivers (HR 1.97, p = 0.05). Survival outcomes were not impacted by BRAF mutation subtype functional class. Conclusions Patients with BRAF-mutated NSCLC have an inferior prognosis, which is not determined by BRAF mutation functional class. In contrast to NSCLC with other tractable driver mutations, BRAF-mutated NSCLC exhibit high susceptibility to immune checkpoint inhibitors.

Colorectal cancer is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, particularly in advanced colorectal cancer. Regulatory T cells (Treg) are increased in the peripheral blood and tumor tissue of patients with colorectal cancer. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8+ T-cell–mediated antitumoral immunity in murine colorectal cancer models. However, before considering therapies on targeting Tregs in patients with cancer, detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here, we demonstrate in a murine model of inflammation-induced colorectal cancer that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human colorectal cancer lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15+ Tregs have a Th17-like phenotype, thereby producing IL17 and TNFα. Gpr15 deficiency repressed Treg infiltration in colorectal cancer, which paved the way for enhanced antitumoral CD8+ T-cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T-cell–mediated antitumoral immunity in colorectal cancer. Significance: The G protein–coupled receptor 15, an unconventional chemokine receptor, directs Tregs into the colon, thereby modifying the tumor microenvironment and promoting intestinal tumorigenesis. See related commentary by Chakraborty and Zappasodi, p. 2817

Purpose Physical activity (PA) is recommended to improve advanced cancer patients’ (ACP) physical functioning, fatigue, and quality of life. Yet, little is known about ACPs’ attitude towards PA and its influence on fatigue and depressiveness over a longer period. This prospective, non-interventional cohort study examined ACPs’ fatigue, depression, motivation, and barriers towards PA before and after 12 months of treatment among ACP Methods Outpatients with incurable cancer receiving treatment at a German Comprehensive Cancer Center reporting moderate/severe weakness/tiredness during self-assessment via MIDOS II were enrolled. Fatigue (FACT-F), depression (PHQ-8), cancer-related parameters, self-assessed PA behavior, motivation for and barriers against PA were evaluated (T0). Follow-up data was acquired after 12 months (T1) using the same questionnaire. Results At follow-up, fatigue (p=0.017) and depressiveness (p=0.015) had increased in clinical relevant extent. Physically active ACP did not show significant progress of FACT-F (p=0.836) or PHQ-8 (p=0.799). Patient-reported barriers towards PA remained stable. Logistic regression analyses identified motivation as a positive predictor for PA at both time points (T0, β=2.152, p=0.017; T1, β =2.264, p=0.009). Clinically relevant depression was a negative predictor for PA at T0 and T1 (T0, β=−3.187, p=0.044; T1, β=−3.521, p=0.041). Conclusion Our findings emphasize the importance of psychological conditions in physical activity behavior of ACP. Since psychological conditions seem to worsen over time, early integration of treatment is necessary. By combining therapy approaches of cognitive behavioral therapy and exercise in interdisciplinary care programs, the two treatment options might reinforce each other and sustainably improve ACPs’ fatigue, physical functioning, and QoL. Trial registration German Register of Clinical Trials, DRKS00012514, registration date: 30.05.2017

Purpose The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal. New cytotoxic agents such as nab-paclitaxel and liposomal irinotecan (nal-Iri) have extended the armamentarium of therapeutic options in the last years. Nowadays, sequential therapeutic strategies with moderately toxic chemotherapeutic protocols can be administered to the patients. However, prognostic and predictive biomarkers are still missing to identify those patients, which profit most from a “continuum of care” concept rather than receiving intensive first-line protocols such as FOLFIRINOX. To this end, we retrospectively evaluated the impact of the systemic inflammation as one essential hallmark of cancer in patients with advanced PDAC treated with sequential systemic. Methods A cohort of 193 PDAC patients treated at our center from January 2005 to August 2011 were retrospectively evaluated for the following systemic inflammatory response (SIR) markers: neutrophil–lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR) C-reactive protein (CRP), and the modified Glasgow Prognostic Score (mGPS). SIR markers were correlated with clinico-pathological findings, response to chemotherapy and overall survival (OS) using Kaplan–Meier curves and Cox proportional models. Results All evaluated SIR markers were significantly associated with OS in patients with metastatic disease but not in patients with locally advanced PDAC. Interestingly, all SIR markers were only prognostic in patients not receiving antibiotics as surrogate marker for systemic bacterial infections. Based on the evaluated SIR markers, we propose a new Systemic Inflammation Score (SIS), which significantly correlated with reduced OS (HR: 3.418 (1.802–6.488, p p = 0.028). Conclusion Routinely assessed SIR biomarkers have potential to support therapeutic decision making in patients with metastatic PDAC.

Background Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed i...

Summary Background Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. Methods ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov , NCT03037385 , and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. Findings Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion–positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48–89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46–73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52–100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. Interpretation Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. Funding Blueprint Medicines.

3566 Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.

The tumor immune microenvironment (TME) represents a key determinant for responses to cancer treatment. However, the immune phenotype of highly proliferative gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is still largely elusive. In this retrospective study, we characterized the TME of high-grade (G3, Ki-67 > 20%) GEP-NEN. We analyzed formalin-fixed paraffin-embedded samples from 37 patients with GEP-NEN G3 by immunohistochemistry and multiplex immunofluorescence to address the abundance and spatial interaction of relevant immune subsets. We focused on the expression of immune checkpoint molecules PD-1 and PD-L1, the cytotoxic T-cell marker CD8, and the tumor-associated macrophage marker CD206. Findings were correlated with overall survival (OS) from the date of a cancer diagnosis. Patients with PD-L1-positive tumors (CPS ≥ 1) and intense PD-1+CD8+ immune cell infiltration showed the most favorable median OS. Multiplex immunofluorescence staining of ten representative tissue samples illustrated intratumoral heterogeneity of PD-L1 expression. Dense PD-1+CD8+ immune cell infiltrates were observed in PD-L1-positive tumor regions but not in PD-L1-negative regions. Proximity analysis revealed a spatial interaction between PD-1+CD8+ cells and PD-L1-positive cells. Our data suggest a pre-existing antitumor immune response in the TME in a subgroup of GEP-NEN G3. This supports a targeted clinical exploration of immunotherapeutic approaches.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Introduction: In the era of targeted therapy of lung cancer, availability of adequate specimen samples for molecular analysis is increasingly important. EBUS-TBNA is often used for tissue acquisition, and the choice of the needle might influence the rate of successful molecular analysis. This prospective study evaluated quality and quantity of specimens obtained using different EBUS-TBNA needles. Methods: Consecutive patients with advanced lung cancer referred for EBUS-TBNA were included. A 22G steel needle (N1), a more flexible needle with a nitinol stylus (N2), or a core biopsy needle (N3) were used for EBUS-TBNA. Specimens were placed on a slide and weighed before transfer of tissue into formalin and sending for histopathological analysis, immunohistochemistry and next-generation sequencing (NGS). Tumour cellularity was assessed by an experienced pathologist. Results: 50 patients (28 male;mean 62.9y) with NSCLC (adeno n=38; squamous cell n=5; large cell n=3; other n=4) were included in the analysis. 25, 12 and 13 specimens were obtained with N1,N2 and N3, respectively. Mean specimen weight was 42.6±38.0 mg. Tumour cellularity was 1000 tumour cells in 6, 5, 6, 3, 8, 9 and 12 cases, respectively. Immunohistochemistry could be performed in all but 3 cases (2 with N2, 1 with N3). NGS could be done in 41 cases (82.0%; failure in 2 cases with N1, 6 with N2, 1 with N3). Tumour cellularity, sample weight and rate of successful NGS were significantly lower when EBUS-TBNA was performed with N2. Conclusion: The needle used for EBUS-TBNA had an impact on quantity and quality of tissue obtained for molecular analysis in NSCLC.

Aims Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. Methods and results Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.

Background The optimal treatment for patients with locally advanced non-small-cell lung-cancer (NSCLC) cT4 cN0/1 cM0 is still under debate. The purpose of this study was to examine the long-term survival of cT4 cN0/1 cM0 NSCLC patients undergoing induction chemotherapy and concurrent radiochemotherapy before surgery. Methods All consecutive patients with confirmed NSCLC (cT4 cN0/1 cM0) treated with neoadjuvant chemotherapy, concurrent radiochemotherapy (RT/CTx) (45–46 Gy) and surgical resection between 2000 and 2015 were included. According to the UICC guidelines (8th edition), T4 stage was reanalysed by an expert radiologist. The mediastinal staging was performed by systematic EBUS-TBNA or mediastinoscopy. The primary end-point was overall-survival (OS). The power to detect an increase of early tumour-associated mortality (hazard ratio > 3.5) within the first 5 years after treatment in comparison to late deaths beyond 96 months was >80%. Results Overall, 67 patients were treated with concurrent RT/CTx. T4 criteria were fulfilled by all patients, and multiple T4 criteria by 53 patients. Seventy percent of patients had an initial PET/CT staging. The median follow-up period was 134 months. OS rates at 2, 5, 10 and 15 years were 83.6 ± 4.5%, 65.4 ± 5.9%, 53.3 ± 6.3% and 36.6 ± 6.8%, respectively. A total of 44.8% of patients achieved a pathologic complete response. In multivariable analysis, ypT category was the most predictive factor. OS at 5 years for ypT0 (n = 31) was 80.5%, and ypT1 (n = 11) was 62.5%. Main sites of failure were brain and pulmonary metastases in seven and three patients, respectively. The intercurrent annual death rate was estimated from the survival curve beyond 96 months and was found to be 4.75% (95% CI 2.40–9.27%). No significant increased mortality was observed during the first 5 years (annual death rate: 8.31% [95% CI 5.60–12.24%], hazard-ratio = 1.72 [95% CI 0.81–3.65]). Conclusions The effectiveness of this trimodality schedule is high in patients with cT4 cN0/1 cM0 NSCLC with excellent local control rates. Considering the annual death rate beyond 8 years of survival as an intercurrent death rate due to comorbidity, this treatment schedule reduces annual mortality to background even in the first 5 years after therapy.

Purpose Diagnosis and treatment of breast cancer have changed profoundly over the past 25 years. The outcome improved dramatically and was well quantified for early stage breast cancer (EBC). However, progress in the treatment of metastatic disease has been less convincingly demonstrated. We have studied survival data of patients with metastatic breast cancer (MBC) from a large academic cancer center over a period of 20 years. Methods Data from 1033 consecutive MBC patients who were treated at the Department of Medical Oncology of the West German Cancer Center from January 1990 to December 2009 were retrospectively analyzed for overall survival (OS) and risk factors. Patients were grouped in 5-year cohorts, and survival parameters of each cohort were compared before and after adjustment for risk factors. Results Overall survival of patients with MBC treated at specialized center has significantly improved from 1990 to 2010 (hazard ratio 0.7, 95%CI 0.58–0.84). The increments in OS have become less profound over time (median OS 1990–1994: 24.2 months, 1995–1999: 29.6 months, 2000–2004: 36.5 months, 2005–2009: 37.8 months). Conclusion Survival of patients with MBC has improved between 1990 and 2004, but less from 2005 to 2009. Either this suggests an unnoticed shift in the patient population, or a lesser impact of therapeutic innovations introduced in the most recent period.

Malignant pleural effusion (MPE) confers dismal prognosis and has limited treatment options. While immune-checkpoint inhibition (ICI) proved clinical efficacy in a variety of malignancies, data on the prognostic role of PD-L1 in MPE is scarce. We retrospectively studied PD-L1 tumour proportion score and Ki-67 index in pleural biopsies or cytologies from 123 patients (69 lung cancer, 25 mesothelioma, and 29 extrathoracic primary malignancies). Additionally, the impact of C-reactive protein (CRP) and platelet count was also analysed. Median overall survival (OS) after MPE diagnosis was 9 months. Patients with PD-L1 positive tumours (≥1%) had significantly shorter OS than patients with negative PD-L1 status (p = 0.031). CRP and Ki-67 index were also prognostic and remained independent prognosticators after multivariate analysis. Interestingly, Ki-67 index and CRP influenced the prognostic power of PD-L1. Finally, patients receiving ICI tended to have a longer median OS and CRP - but not PD-L1 - was a significant prognosticator in this subgroup. In summary, histological and circulating biomarkers should also be taken into account as potential biomarkers in ICI therapy and they may have an impact on the prognostic power of PD-L1. Our findings might help personalizing immune-checkpoint inhibition for patients with MPE and warrant further prospective validation.

Objective Current predictive biomarkers for PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-directed immunotherapy in non-small cell lung cancer (NSCLC) mostly focus on features of tumour cells. However, the tumour microenvironment and immune context are expected to play major roles in governing therapy response. Against this background, we set out to apply context-sensitive feature selection and machine learning approaches on expression profiles of immune-related genes in diagnostic biopsies of patients with stage IV NSCLC. Methods RNA expression levels were determined using the NanoString nCounter platform in formalin-fixed paraffin-embedded tumour biopsies obtained during the diagnostic workup of stage IV NSCLC from two thoracic oncology centres. A 770-gene panel covering immune-related genes and control genes was used. We applied supervised machine learning methods for feature selection and generation of predictive models. Results Feature selection and model creation were based on a training cohort of 55 patients with recurrent NSCLC treated with PD-1/PD-L1 antibody therapy. Resulting models identified patients with superior outcomes to immunotherapy, as validated in two subsequently recruited, separate patient cohorts (n = 67, hazard ratio = 0.46, p = 0.035). The predictive information obtained from these models was orthogonal to PD-L1 expression as per immunohistochemistry: Selecting by PD-L1 positivity at immunohistochemistry plus model prediction identified patients with highly favourable outcomes. Independence of PD-L1 positivity and model predictions were confirmed in multivariate analysis. Visualisation of the models revealed the predictive superiority of the entire 7-gene context over any single gene. Conclusion Using context-sensitive assays and bioinformatics capturing the tumour immune context allows precise prediction of response to PD-1/PD-L1-directed immunotherapy in NSCLC.

Background The multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC). Patients and methods Patients received FOLFOX6 with cetuximab (500 mg/m2) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location. Results In total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval [CI], 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months. Conclusions This study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167 .

Background Deregulated signal transduction pathways play a key role in development, progression and therapeutic resistance of non-small cell lung cancers (NSCLC). The purpose of this study is to assess the downstream markers of two well-characterized pathways and to correlate them with clinical outcome. Design 670 patients with metastatic NSCLC were prospectively enrolled in a comprehensive biomarker profiling program at a single center from 2012 to 2016. Phosphorylation of extracellular signal-regulated kinase (p-ERK), and protein kinase B (p-AKT) was assessed by standardized immunohistochemistry. Product of scores for quantity and quality of staining were calculated (immunoreactive score, 0–9). Somatic mutations of Kirsten rat sarcoma viral oncogene homolog [KRAS], epithelial growth factor receptor [EGFR], v-Raf murine sarcoma viral oncogene homolog B [BRAF] and phosphatidylinositol 3-kinase [PIK3CA]) were detected by Sanger (2012-03/2015) and amplicon NGS (04/2015-02/2016). Patients enrolled during the first year (2012) were used as discovery cohort. Patients enrolled from 2013 to 02/2016 were used as validation cohort. Clinical data were retrieved from the electronic medical records and were analyzed retrospectively. Results Using a discovery cohort, we identified an immunoreactive score of p-ERK ≥3 to be prognostically relevant. The validation cohort confirmed that higher levels of p-ERK correlated with worse overall survival (OS) and higher proportion of RAS mutations. Multivariate analysis including established risk factors such EGFR, ALK or ROS mutations and metastatic disease showed a trend of a detrimental effect of high p-ERK on OS (HR 1.23, CI 0.94–1.59, p = 0.131 for p-ERK immunoreactive score ≥3) and time to treatment failure after first-line therapy in the validation cohort. Phosphorylated AKT did not correlate with clinical outcome. Conclusion While serving as a prognosticator in univariate analysis, highly phosphorylated ERK does not convey a significant prognostic effect for OS in the presence of other prognostic factors. Phosphorylated ERK indicates a higher activity of RAS in advanced NSCLC.

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234–0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177–3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

In the METROS trial, Landi and colleagues evaluated the efficacy of crizotinib in advanced non–small cell lung cancer (NSCLC) harboring ROS1 rearrangements or MET dysregulation ([1][1]). A total of 505 patients were screened and 10 patients entered the trial with cancers harboring MET exon 14

Patients (pts) with locally advanced (LAPC) or metastatic pancreatic ductal adenocarcinoma (mPDAC) have a dismal prognosis. Recently, new combination chemotherapies such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated superiority over gemcitabine monotherapy. However, a substantial proportion of pts cannot tolerate these intensive front-line protocols. Moreover, the long-term superiority of multiagent protocols over less intensive strategies remains to be shown. To provide a benchmark for future studies, we analyzed the outcome of patients with LAPC or mPDAC treated at the West German Cancer Center before the FOLFIRINOX/nab-paclitaxel + gemcitabine era. This retrospective analysis included 201 consecutive pts with LAPC and mPDAC treated between 2007 and 2011. Efficacy parameters were correlated with type of chemotherapy, number of treatment lines and clinicopathological parameters. Gemcitabine monotherapy was given as first-line therapy in 51.1%, whereas 48.9% received combination chemotherapies such as gemcitabine/oxaliplatin or FOLFOX. Patients received a median of two lines of treatment, with 54.8% receiving second-line and 37.9% receiving third- and further-line therapies. There was no significant difference between gemcitabine monotherapy and combination therapies. Despite moderate activity of first-line treatment, median overall survival for LAPC was 11.3 months and 8.7 months for mPDAC. Multivariate analysis identified age and number of treatment lines as prognostic markers. The long-term outcome of unselected pts with LAPC and mPDAC treated before the introduction of aggressive multiagent chemotherapy protocols compares favorably with the results of contemporary benchmark trials. This suggests a multifactorial benefit from interdisciplinary care provided over sequential treatment lines at high volume expert centers.

Introduction: Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (68Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of 90Y-labelled FAPI-46 (90Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUVmax ≥ 10 in more than 50% of all lesions. If tolerated, post-therapeutic 90Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and 90Y-FAPI-46 PET scans at multiple time-points were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy 90Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28 Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which thrombocytopenia was most prevalent (N = 6; 67%), whereas other G3/G4 laboratory-based adverse events were N ≤ 2. No acute toxicities attributed to 90Y-FAPI-46 were noted. Radiographic disease control was noted in three patients (33 %). Conclusion: FAP-targeted RLT with 90Y-FAPI-46 was well tolerated with a low rate of attributable adverse events. Low radiation doses to organs at risk suggest feasibility of repeat cycles of 90Y-FAPI-46. We observe signs of clinical activity, but further studies are warranted to determine efficacy and toxicity profile in a larger cohort.

Introduction In LUX-Lung 3 and LUX-Lung 6, afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with tumors harboring common epidermal growth factor receptor (EGFR) mutations (Del19/L858R) and significantly improved overall survival (OS) in patients with tumors harboring Del19 mutations. Patient-reported outcomes stratified by EGFR mutation type are reported. Patients and Methods Lung cancer symptoms and health-related quality of life (QoL) were assessed every 21 days until progression using the EORTC Quality of Life Core Questionnaire C30 and its lung cancer-specific module, LC13. Analyses of cough, dyspnea, and pain were prespecified and included analysis of percentage of patients who improved on therapy, time to deterioration of symptoms, and change over time. Global health status (GHS)/QoL was also assessed. Analyses were conducted for all patients with tumors harboring Del19 or L858R mutations and were exploratory. Results Compared with chemotherapy, afatinib more commonly improved symptoms of, delayed time to deterioration for, and was associated with better mean scores over time for cough and dyspnea in patients with Del19 or L858R mutations. All three prespecified analyses of pain showed a trend favoring afatinib over chemotherapy. In both Del19 and L858R mutations, afatinib was also associated with improvements in GHS/QoL. Longitudinal analyses demonstrated statistically significant improvements in GHS/QoL for afatinib over chemotherapy for patients with tumors harboring Del19 mutations or L858R mutations. Conclusions These exploratory analyses suggest first-line afatinib improved lung cancer-related symptoms and GHS/QoL compared with chemotherapy in patients with non-small-cell lung cancer with tumors harboring common EGFR mutations, with benefits in both Del19 and L858R patients. When considered with OS (Del19 patients only) and PFS benefits, these findings substantiate the value of using afatinib over chemotherapy in these patient groups. Electronic supplementary material The online version of this article (10.1007/s40271-017-0287-z) contains supplementary material, which is available to authorized users.

Background Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33–74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995–1.015), P=0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986–1.012), P=0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No. Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

DNA damage-induced cell death is a major effector mechanism of radiotherapy. Aberrant expression of anti-apoptotic BCL-2 family proteins is frequently observed in lung cancers. Against this background, we studied radioresistance mediated by BCL-2 family proteins at the mechanistic level and its potential as target for radiochemotherapy. Lung cancer models stably expressing BCL-xL or MCL-1 were irradiated to study cell death, clonogenic survival, and DNA repair kinetics in vitro, and growth suppression of established tumors in vivo. Additionally, endogenous BCL-xL and MCL-1 were targeted by shRNA or pharmacologic agents prior to irradiation. Radiation exposure induced apoptosis at negligible levels. Yet, anti-apoptotic BCL-xL and MCL-1 expression conferred short-term and long-term radioresistance in vitro and in vivo. Radioresistance correlated with pertubations in homologous recombination repair and repair of DNA double-strand breaks by error-prone, alternative end-joining. Notably, genetic or pharmacologic targeting of BCL-xL or MCL-1 effectively sensitized lung cancer cells to radiotherapy. In addition to directly suppressing apoptosis, BCL-2 family proteins confer long-term survival benefits to irradiated cancer cells associated with utilization of error-prone repair pathways. Targeting BCL-xL and MCL-1 is an attractive strategy for improving lung cancer radiotherapy.

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610–9. ©2017 AACR.See related commentary by Sundar et al., p. 558.This article is highlighted in the In This Issue feature, p. 539

OA embargo Objectives Chromosomal rearrangements involving ROS1 define a rare entity of lung adenocarcinomas with exquisite sensitivity to molecularly targeted therapy. We report clinical outcomes and genomic findings of patients with ROS1-positive lung cancer who were prospectively identified within a multiplex biomarker profiling program at the West German Cancer Center. Methods Standardized immunohistochemical (IHC) analysis, fluorescence in situ hybridization (FISH), and hotspot mutation analyses were performed in 1345 patients with advanced cancer, including 805 patients with metastatic lung adenocarcinoma. Clinical and epidemiological data were retrieved from the institutional database. Results ROS1 positivity by IHC analysis was detected in 25 patients with lung cancer (4.8% of lung adenocarcinomas), including 13 patients (2.5%) with ROS1 FISH positivity with a cutoff of at least 15% of events. Of the ROS1 IHC analysis–positive cases, 36% presented with concomitant oncogenic driver mutations involving EGFR (six cases, five of which were clinically validated by response to EGFR-targeting agents), KRAS (two cases), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), and BRAF. Three cases initially classified as ROS1 FISH–negative passed the threshold of 15% positive events when repeat biopsies were analyzed at progression. The median overall survival of the ROS1-positive patients (104 months) was significantly superior to that of the 261 patients with EGFR/anaplastic lymphoma kinase/ROS1–negative lung adenocarcinoma (24.4 months, p = 0.044). Interestingly, the overall survival of the 13 ROS1-positive patients with lung cancer from initiation of pemetrexed-based chemotherapy was significantly prolonged when compared with that of 169 pemetrexed-treated patients with EGFR/anaplastic lymphoma kinase/ROS1–negative adenocarcinoma (p = 0.01). Conclusions ROS1-positive metastatic lung adenocarcinomas frequently harbor concomitant oncogenic driver mutations. Levels of ROS1 FISH–positive events are variable over time. This heterogeneity provides additional therapeutic options if discovered by multiplex biomarker testing and repeat biopsies. © 2016 International Association for the Study of Lung Cancer

Summary Background The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib. Methods We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50–800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1–3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited. Findings Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3–4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25–36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6–23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration. Interpretation Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment. Funding Bayer AG.

Objectives With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. Methods Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan–Meier estimates. Results Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years. Conclusions Most patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.

Background Thymic epithelial and neuroendocrine carcinomas are rare malignancies, and only a few prognosticators are defined. Surgery is the mainstay of treatment, and complete resection contributes to superior outcome. Systematic lymph node dissection is not routinely performed in thymic malignancies. The aim of this study was to assess the impact of histologically confirmed lymph node metastases on the outcome after thymectomy. Methods We identified 53 patients with thymic epithelial or neuroendocrine carcinomas who underwent surgical resection at our center between 1999 and 2016. The clinical follow-up was retrospectively collected, and the impact of clinicopathologic factors on overall survival was analyzed. Results Ninety-one percent of the patients were treated taking a multimodal approach. Median overall survival was 11.3 years. Lymph node metastases were identified in 16 patients (30.2%; 11 pN1 and 5 pN2). Lymph node metastasis was associated with inferior overall survival (hazard ratio [HR] 3.03, 95% confidence interval [CI]: 1.03 to 8.87, p = 0.044). Masaoka-Koga stage (4 versus 1 to 3) was another significant prognosticator (HR 7.01, 95% CI: 2.52 to 19.50, p = 0.0002). Organ metastases were present in 18 patients at the time of thymectomy and were associated with inferior outcome (HR 5.8, 95% CI: 2.04 to 16.79, p = 0.001). Conclusions This retrospective, single-center analysis demonstrates a high rate of lymph node metastasis in resectable thymic neuroendocrine tumors or carcinomas. Positive lymph nodes are associated with an inferior outcome. Prospective studies are warranted to explore whether this outcome can be improved by systematic lymphadenectomy and adjuvant therapies. Nevertheless, lymphadenectomy provides optimal staging and should be a routine part of surgery for patients with thymic malignancies.

According to the ACRIN 6668/RTOG 0235 trial, pretreatment metabolic tumour volume (MTV) as detected by 18F-fluorodeoxyglucose PET/CT is a prognostic factor in patients with stage III non-small-cell lung cancer (NSCLC) after definitive radiochemotherapy (RCT). To validate the prognostic value of MTV in patients with stage III NSCLC after RCT, we analysed mature survival data from the German phase III trial ESPATUE. This analysis included patients who were staged by PET/CT and who were enrolled in the ESPATUE trial, a randomized study comparing definitive RCT (arm A) with surgery (arm B) after induction chemotherapy and RCT in patients with resectable stage IIIA/IIIB NSCLC. Patients refusing surgery and those with nonresectable disease were scheduled to receive definitive RCT. MTV was measured using a fixed threshold-based approach and a model-based iterative volume thresholding approach. Data were analysed using proportional hazards models and Kaplan-Meier survival functions. MTV as a continuous variable did not reveal differences in survival between the 117 patients scheduled to receive definitive RCT and all 169 enrolled patients who underwent pretreatment PET/CT (p > 0.5). Five-year survival rates were 33% (95% CI 17–49%) in patients scheduled for definitive RCT with a high MTV (>95.4 ml) and 32% (95% CI: 22–42%) in those with a low MTV. The hazard ratio for survival was 0.997 (95% CI 0.973–1.022) per 10-ml increase in MTV and the slope was significantly shallower than that in the ACRIN 6668/RTOG 0235 trial (random effects model, p = 0.002). There were no differences in MTV size distributions between the ACRIN and ESPATUE trials (p = 0.97). Patients with stage III NSCLC and a large MTV in whom definitive RCT had a particularly good survival in the ESPATUE trial. Treatment individualization according to MTV is not supported by this study. The ESPATUE and ACRIN trials differed by the use of cisplatin-containing induction chemotherapy and an intensified radiotherapy regimen that were particularly effective in patients with large MTV disease.

Background Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. Patients and methods Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. Results From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. Conclusions Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. ClinicalTrials.gov number NCT01197885.