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Background Cancer therapy–related cardiac dysfunction (CTRCD) is a challenging and life-threatening complication of many chemotherapeutic regimens. CTRCD prevention, diagnosis, and therapy require both careful interdisciplinary assessment and management. For patients with CTRCD, current guidelines of the European Society of Cardiology (ESC) recommend an angiotensin-converting-enzyme inhibitor in combination with a beta-blocker. Recent studies indicate a beneficial effect of sacubitril/valsartan in this patient population. Case summary A 68-year-old female patient with a pleural epithelioid angiosarcoma developed heart failure with reduced ejection fraction and elevated serum biomarkers following doxorubicin treatment. After implementation of a recommended cardioprotective medical therapy including torasemide, ramipril, carvedilol, and spironolactone, the patient suffered two cardiac decompensations within 4 weeks after initiation of a paclitaxel regimen and pleural radiation therapy due to pain exacerbation. Despite a continuous application of the cardioprotective medical treatment regimen, no improvement of left-ventricular ejection fraction (LVEF) was detected in a 4-month follow up. Interestingly, after omitting ramipril and implementing low-dose sacubitril/valsartan (26/24 mg), we observed a decrease in serum biomarkers within 3 months as well as a significant improvement of LVEF within 6 months. After nearly 10 months of disease stabilization under paclitaxel, the patient suffered progressive cancer disease and deceased 1 week later after the initiation of a therapeutic attempt with pazopanib. Discussion This case report highlights the importance of interdisciplinary care in cancer patients as well as the promising role of (low-dose) sacubitril/valsartan in patients with CTRCD even in the setting of delayed initiation.

Introduction: Thymic epithelial tumors (TETs) are very rare. Thymoma A and AB have a better prognosis than more aggressive thymoma B, thymic carcinoma (TC) and neuroendocrine tumors of the thymus (NET). While previous efforts such as TCGA have mainly characterized thymomas (Radovich et al., Cancer Cell 2018), the molecular landscape of TCs and NETs is still elusive. Patients and Methods: Between 03/2014 and 07/2020, we enrolled 44 TET patients (27 TCs, 11 thymomas, 6 NETs) in a prospective observational study (MASTER) conducted by the National Center for Tumor Diseases (NCT) Heidelberg, NCT Dresden and the German Cancer Consortium (DKTK). MASTER applied whole genome/exome sequencing (WGS, n=22; WES, n=22), transcriptome (n=40) and germline analysis to inform therapy recommendations by a dedicated molecular tumor board (MTB). We systematically gathered follow-up data to evaluate outcome and compared progression-free survival (PFS) of the first treatment according to an MTB recommendation (PFS2) to the last prior systemic treatment (PFS1) in each patient (PFS ratio). Results: Tumor mutational burden (TMB) was low (median=0.99 mutations/Mb, range 0.08-3.48) but higher than in TCGA (p 6 months and a PFS ratio > 1.3. The best outcome was achieved using imatinib in a patient with a KIT mutation (p.W557R). After progression, the MTB recommended ponatinib based on a secondary KIT mutation (p.V654A). The patient was still on ponatinib when the observation period ended. Conclusion: We demonstrate that comprehensive molecular analysis provides clinically relevant information in a subgroup of TET patients. Thymoma, TCs, and NETs present with different molecular characteristics. Distinction between immunologically hot and cold TCs may have value for risk stratification and therapeutic strategies. PARP inhibition could be a potential new treatment option in a small subgroup of TETs. Molecular testing of KIT, germline analysis and genetic counseling should be recommended for all patients with advanced TETs. Citation Format: Lino Möhrmann, Lysann Rostock, Małgorzata Oleś, Arne Jahn, Marie Arlt, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Elena E. Wolf, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E. Heilig, Veronica Teleanu, Daniel B. Lipka, Andreas Mock, Ivan Jelas, Damian T. Rieke, Marcel Wiesweg, Melanie Boerries, Anna L. Illert, Alexander Desuki, Thomas Kindler, Angela M. Krackhardt, C. Benedikt Westphalen, Heidrun Grosch, Leonidas Apostolidis, Albrecht Stenzinger, Irina A. Kerle, Christoph Heining, Daniel Hübschmann, Evelin Schröck, Stefan Fröhling, Hanno Glimm. Genomics-based personalized oncology of advanced thymic epithelial tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 926.

BackgroundBNT211 is a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen Claudin-6 (CLDN6). Preclinical studies demonstrated that combining these engineered cells with a CAR-T cell Amplifying RNA Vaccine (CARVac) leads to in vivo expansion of adoptively transferred CAR-T cells, resulting in their improved persistence and functionality.MethodsThis first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with separate CLDN6 CAR-T cell dose escalations (single flat-dose) for monotherapy (part 1) and the combination with CARVac (part 2) based on 3 dose levels (DL). In part 2, CARVac is applied every 3 weeks starting at day 4 post transplantation including a one-step intra-patient dose escalation. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0 or 1 are eligible for recruitment.ResultsAs of July 23rd 2021, 8 patients have been treated. DL1 of part 1 has been completed, while dosing of part 1 DL2 and part 2 DL1 is ongoing. One patient with cancer of unknown primary was treated with a dose below DL1 in combination with CARVac; the underlying diseases of the other 7 treated patients were testicular, ovarian and endometrial cancer as well as soft-tissue sarcoma. No acute or dose-limiting toxicities and no serious adverse events related to the drug product have been reported. Manageable cytokine release syndrome (CRS, grade 1-2, the latter managed with Tocilizumab) without any signs of neurotoxicity have been observed in both patients of part 1 DL2. Only transient and moderate elevations of IL-6 and CRP serum levels occurred in remaining patients. Notably, administration of CARVac resulted in transient flu-like symptoms resolving within 24h. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment followed by decline after day 17. Further expansion was noted in two patients with liver metastases accompanied by elevated levels of ALT, AST and AP, while total bilirubin was not affected. First tumor assessment 6 weeks after transplantation available for 5/8 patients revealed 4 SD (3 transitioned into PD after an additional 6-18 weeks) and 1 PD. Strikingly, three patients showed initial tumor shrinkage according to RECIST1.1 (reduction of target sum: -18%, -21% and -27%).ConclusionsCLDN6 CAR-T cells +/- CARVac show a favorable safety profile at doses tested and encouraging signs of efficacy. Updated data from open cohorts and especially for combination with CARVac will be presented.AcknowledgementsBNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH.Trial RegistrationClinicaltrialsgov: NCT04503278ReferencesN/A Ethics ApprovalEthics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial.ConsentN/A

Background Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translating experimental treatments into standard care. Patients and methods Continuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label phase II trial for adults with pretreated, locally advanced, or metastatic solid tumors. Based on the evaluation by a molecular tumor board, patients are assigned to combinations of six molecularly targeted agents and a programmed death-ligand 1 (PD-L1) antagonist within seven study arms focusing on (i) BRAF V600 mutations; (ii) ERBB2 amplification and/or overexpression, activating ERBB2 mutations; (iii) ALK rearrangements, activating ALK mutations; (iv and v) activating PIK3CA and AKT mutations, other aberrations predicting increased PI3K–AKT pathway activity; (vi) aberrations predicting increased RAF–MEK–ERK pathway activity; (vii) high tumor mutational burden and other alterations predicting sensitivity to PD-L1 inhibition. The primary endpoint is the disease control rate (DCR) at week 16; secondary and exploratory endpoints include the progression-free survival ratio, overall survival, and patient-reported outcomes. Using Simon’s optimal two-stage design, 14 patients are accrued for each study arm. If three or fewer patients achieve disease control, the study arm is stopped. Otherwise, 11 additional patients are accrued. If the DCR exceeds 7 of 25 patients, the null hypothesis is rejected for the respective study arm. Conclusions CRAFT was activated in October 2021 and will recruit at 10 centers in Germany. Trial registration numbers EudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521., Highlights • Actionable genetic alterations are detected in many cancers with unknown efficacy of the corresponding targeted therapies. • CRAFT, an open-label multicenter phase II trial, uses six molecularly targeted agents and a PD-L1 antagonist in seven treatment arms. • Patient allocation to trial arms is based on evaluation of molecular tumor characteristics by the German Cancer Consortium. • The in-depth molecular characterization helps to understand mechanisms underlying primary and acquired therapy resistance. • The CRAFT trial has been active in Germany since October 2021 and will open at 10 sites during 2022.

Background Amyloidosis is a multi-systemic disease resulting from deposition of misfolded proteins as insoluble fibrils in the interstitium of affected organs including the heart, subsequently leading to organ failure. Cardiac involvement is predominantly observed in light chain (AL) amyloidosis and wild-type transthyretin (ATTRwt) amyloidosis. Purpose We aimed to investigate prevalence and prognostic implications of cardiac amyloidosis of any etiology on outcomes of hospitalized patients with heart failure (HF) in Germany. Methods We analyzed data of the German nationwide inpatient sample (2005–2018) of patients hospitalized for HF (including myocarditis with HF and heart transplantation with HF). HF patients with amyloidosis (defined as cardiac amyloidosis [CA]) were compared with those HF patients without amyloidosis and impact of CA on outcomes was assessed (source: Research Data Center (RDC) of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005–2018, and own calculations). Results During this fourteen-year observational period 5,478,835 hospitalizations of HF patients were analyzed. Amyloidosis was coded in 5,407 hospitalizations of HF patients (0.1%). Prevalence of CA was 1.87 hospitalizations per 100,000 German population. CA patients were younger (75.0 [IQR 67.0/80.0] vs. 79.0 [72.0–85.0] years, p Conclusions CA was identified as an independent risk factor for complications and in-hospital mortality in HF patients. Physicians should be aware of this issue concerning treatments and monitoring of CA-patients. Funding Acknowledgement Type of funding sources: None.

Background: BNT211 comprises two drug products, a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen claudin 6 (CLDN6) and a CAR-T cell-Amplifying RNA Vaccine (CARVac). In mice, CARVac mediates expansion of adoptively transferred CAR-T cells, improving their persistence and functionality. BNT211 aims to establish CAR-T cell therapy for CLDN6-positive solid tumors. Methods: This first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with CLDN6 CAR-T cell dose escalations for both monotherapy (Part 1) and combination with CARVac (Part 2) following lymphodepletion. In Part 2, CARVac is applied q2/3w up to 100 days post CAR-T cell transfer, including a one-step intra-patient dose escalation followed by q6w maintenance dosing. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0-1 are eligible for recruitment. Results: As of 19th Jan 2022, 16 patients have been treated, with CAR-T cell transfer performed at dose levels (DLs) 1 and 2 for parts 1 and 2. In total, 37 ≥G3 AEs related to the drug product (mainly cytopenia, or transaminase and lipase elevations without clinical correlates) and 2 DLTs (G4 cytopenia at DL2, part 1 and G4 hemophagocytic lymphohistiocytosis at DL2, part 2) were reported (all resolved). Pronounced cytopenia occurred in patients with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplantation. For these patients a lymphodepletion-free/reduced cohort was recently opened. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment in all patients, with peak engraftment around day 17. Manageable cytokine release syndrome (G1-2) without any signs of neurotoxicity was observed in 8 patients. Administration of CARVac resulted in transient flu-like symptoms resolving within 24 h. Preliminary efficacy data of 12 evaluable patients 6 weeks after infusion showed 5 patients with PRs (with 39-49% shrinkage of target lesions), 6 with SD and 1 patient with PD (ORR 42%; DCR 92%), with responses seen in testicular and ovarian cancer patients. At 12 weeks, 5 of the 6 patients with PRs showed deepening of responses (50-73% shrinkage). In addition, one testicular cancer patient was treated with a 50% lymphodepletion regime and showed PR after 6 weeks. Conclusions: CLDN6 CAR-T cells ± CARVac show an acceptable safety profile at doses tested and encouraging signs of clinical activity. Data from the completed dose escalation phase will be presented. Acknowledgements: BNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH. Trial registration: Clinicaltrials.gov: NCT04503278. Ethics approval: Ethics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial. Citation Format: John BAG Haanen, Andreas Mackensen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Alexander Desuki, Florian Lüke, Erol Wiegert, Catrine Schulz, Benjamin Rengstl, Liane Preussner, Özlem Türeci, Ugur Sahin. BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT002.

Introduction In contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting. Methods We retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results ICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months. Conclusions ICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.

Background Extensive sequencing of tumor tissues has greatly improved our understanding of cancer biology over the past years. The integration of genomic and clinical data is increasingly used to select personalized therapies in dedicated tumor boards (Molecular Tumor Boards) or to identify patients for basket studies. Genomic alterations and clinical information can be stored, integrated and visualized in the open-access resource cBioPortal for Cancer Genomics. cBioPortal can be run as a local instance enabling storage and analysis of patient data in single institutions, in the respect of data privacy. However, uploading clinical input data and genetic aberrations requires the elaboration of multiple data files and specific data formats, which makes it difficult to integrate this system into clinical practice. To solve this problem, we developed cbpManager. Results cbpManager is an R package providing a web-based interactive graphical user interface intended to facilitate the maintenance of mutations data and clinical data, including patient and sample information, as well as timeline data. cbpManager enables a large spectrum of researchers and physicians, regardless of their informatics skills to intuitively create data files ready for upload in cBioPortal for Cancer Genomics on a daily basis or in batch. Due to its modular structure based on R Shiny, further data formats such as copy number and fusion data can be covered in future versions. Further, we provide cbpManager as a containerized solution, enabling a straightforward large-scale deployment in clinical systems and secure access in combination with ShinyProxy. cbpManager is freely available via the Bioconductor project at https://bioconductor.org/packages/cbpManager/ under the AGPL-3 license. It is already used at six University Hospitals in Germany (Mainz, Gießen, Lübeck, Halle, Freiburg, and Marburg). Conclusion In summary, our package cbpManager is currently a unique software solution in the workflow with cBioPortal for Cancer Genomics, to assist the user in the interactive generation and management of study files suited for the later upload in cBioPortal.