Search

Background: Renal cell carcinoma is one of the most common malignant tumors in Germany with an increasing incidence. Drug therapy is indicated in relapsed or metastatic disease., Materials and Methods: The article is based on the content of the recent guidelines and a selective literature search., Results: Combination therapies based on a checkpoint inhibitor are the current standard in first-line treatment of metastatic renal cell carcinoma. The median overall survival could thus be extended to > 50 months. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score is used for risk classification. When selecting a suitable combination therapy, it is important to consider the advantages and disadvantages for each individual patient. There is currently no standard for follow-up therapies. So far, combination therapies have not shown any significant advantage in second-line treatment. It is recommended to switch to a substance that has not yet been used., Conclusions: Currently, one purely immuno-oncology combination and four combinations of one immune checkpoint inhibitor and one tyrosine kinase inhibitor (TKI) are approved for first-line therapy in Germany. The added value of further intensification of therapy, in particular through triple combinations or further combination therapy in the second line, has not yet been proven., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: T. Hilser: Honorar: IPSEN. C. Darr: Honorar: Janssen-Cilag, Ipsen; Reisekosten: Janssen-Cilag, Ipsen, Bayer. K. Schlack: Beratungstätigkeit: AAA, Amgen, Apogepha, Astellas, AstraZeneca, Bayer, BMS (personal and institutional), Eisai, EUSA-Pharma, Fosanis, Ipsen, Janssen Cilag, Merck Healthcare, MSD, Novartis (personal and institutional), Pfizer (personal and institutional), Roche; Reisekosten: Sanofi-Aventis, Astra Zeneca, Astellas, Bayer, Janssen Cilag, Ipsen, Merck Healthcare. V. Grünwald: Aktienbesitz: AstraZeneca, Bicycle Therapeutics, Bristol-Myers Squibb, Genmab, MSD; Honorar: Advanced Accelerator Applications/Novartis, Amgen, Apogepha, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, Janssen-Cilag, Merck Serono, MSD Oncology, Ono Pharmaceutical, Pfizer; Beratungstätigkeit: Bristol-Myers Squibb, Cureteq, Debiopharm Group, Eisai, Gilead Sciences, Ipsen, Janssen-Cilag, MSD Oncology, Novartis, Oncorena, PCI Biotech, Pfizer, Synthekine; Forschungsfinanzierung: Amgen (Inst), Bicycle Therapeutics (Inst), Bristol-Myers Squibb (Inst), Gilead Sciences (Inst), Ipsen (Inst), Seagen (Inst); Reisekosten: AstraZeneca, Ipsen, Janssen, Merck Serono, Pfizer. U.-U. Yesilyurt und N. Klümper geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-naïve CUP patients., Methods: Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines., Results: Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1-positive CUP (TPS ≥1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0-18.0; HR 0.3, p < 0.001). The benefit of PD-L1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0-37.0 versus 10 months, 95 %CI 3.1-16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS ≥50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4)., Conclusion: PD-L1 expression associates with favorable survival in checkpoint inhibitor-naïve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients., Methods: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan-Meier (KM) plots were utilized where appropriate., Results: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% ( n = 61). A prior nephrectomy was performed in 60.4% ( n = 58). ECOG 0-1 was 68.8% ( n = 66). A partial response was documented in 43.8% of patients ( n = 42), a stable disease in 32.3% ( n = 31), and a progressive disease in 8.3% ( n = 8) as the best overall response. Response data were not evaluable in 13.5% ( n = 13). The median follow-up time was 12.7 months (95% CI, 10.0-15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% ( n = 79) for all grades and 41.7% ( n = 40) for grades 3-5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand-foot syndrome (29.2%) were the three most frequent AEs of any grade and causality., Discussion/conclusions: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study.

Background: Immunomodulatory therapies are becoming increasingly important in uro-oncology. For this reason, we will probably be increasingly confronted with side effects. In addition, there is an increasing number of combinations with other mechanisms of action. Immune-mediated side effects may occur as a consequence of this therapy. These are different from the side effects of chemotherapy and other targeted therapies and therefore require different treatment strategies., Aim: Based on the current literature, the data on graduation and stage-dependent management will be presented as well as illustrated with examples from practice., Materials and Methods: Literature review on the detection and therapeutic management of adverse events mediated in the setting of immuno-oncologic therapy., Results: Treatment-related events can in principle affect all organ systems. Toxicities in the area of the skin, such as rash or pruritus, hypo- or hyperthyreosis, arthritis, muscle pain and gastrointestinal symptoms are frequently seen. In terms of frequency, most side effects are grade 1 to 2, but grade 3 to 4 toxicities are also generally well treatable if detected early. Rare complications such as neurological toxicities, pneumonitis or carditis can develop a fulminant course if diagnosed too late., Conclusions: Even emergencies are manageable if we know the most important side effects and the therapeutic options. Immune-mediated side effects are of particular importance because they can affect any organ system. However, as long as we consider the possibility of toxicity from checkpoint inhibitors when the patient presents with symptoms, most side effects are easy to treat and therefore manageable., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Cancer of unknown primary (CUP) is a heterogeneous entity with a limited prognosis. Novel prognostic markers are needed for patient stratification in prospective clinical trials exploring innovative therapies. Methods: In CUP patients treated at the West German Cancer Center Essen, the prognostic value of 18 F-FDG PET/CT at the initial diagnostic workup was analyzed by comparing overall survival (OS) in patients who underwent 18 F-FDG PET/CT with those who did not. Results: Of 154 patients with a CUP diagnosis, 76 underwent 18 F-FDG PET/CT at the initial diagnostic workup. The median overall survival (OS) of the full analysis set was 20.0 mo. Within the PET/CT subgroup, an SUV max above 20 was associated with significantly superior OS (median OS, not reached vs. 32.0 mo; hazard ratio, 0.261; 95% CI, 0.095-0.713; P = 0.009). Conclusion: Our retrospective work shows that an SUV max above 20 on 18 F-FDG PET/CT at the initial diagnostic workup is a favorable prognostic factor in patients with CUP. This finding deserves further prospective studies for validation., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials., Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients., Design Setting and Participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards., Outcome Measurements and Statistical Analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method., Results and Limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up., Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC., Patient Summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment., (© 2023 The Author(s).)

Immune-checkpoint-inhibitor (ICI) therapy has been one of the major advances in the treatment of a variety of advanced or metastatic tumors in recent years. Therefore, ICI-therapy is already approved in first-line therapy for multiple tumors, either as monotherapy or as combination therapy. However, there are relevant differences in approval among different tumor entities, especially with respect to PD-L1 testing. Different response to ICI-therapy has been observed in the pivotal trials, so PD-L1 diagnostic testing is used for patient selection. In addition to PD-L1 testing of tumor tissue, liquid biopsy provides a noninvasive way to monitor disease in cancer patients and identify those who would benefit most from ICI-therapy. This overview focuses on the use of ICI-therapy and how it relates to common and potential future biomarkers for patient-directed treatment planning., Competing Interests: C.K. reports consulting fees Apogepha, research funding Advanced Accelerator Applications (Novartis). B.A.H. reports personal fees from ABX, Bayer, LightPoint Medical Inc., Janssen R&D, Bristol-Myers-Squibb and Astellas; research funding from Profound Medical, German Cancer Aid, German Research Foundation, Janssen R&D, Bristol-Myers-Squibb, MSD, Pfizer and Astellas; and travel fees from AstraZeneca, Janssen R&D and Astellas. V.G. reports fees from Astellas, AstraZeneca, BMS, EISAI, Ipsen, Janssen-Cilag, Merck Serono, MSD, Novartis, Pfizer, Roche, and research grants from BMS, Ipsen, MSD and Pfizer. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate cancer, combination therapies of two or three agents of ADT, androgen receptor signaling inhibitors (ARSI) and chemotherapy have been established and led to a significant benefit in overall survival. Additionally, in patients with metastatic castration-resistant prostate cancer, there are many new therapeutic approaches. Chemotherapy alone has been the standard of care in this situation. In the last years, some new therapeutic options have been developed, which led to an improved survival after progression under chemotherapy. These therapies include ARSI, PARP inhibitors and Lu-PSMA radioligand therapy. The use of a bispecific T-cell engager (BiTE) in this setting is a new promising therapeutic approach, which has not been established as standard of care yet. The role of immunotherapy in prostate cancer is still under investigation. Overall, many new treatment options make prostate cancer therapy a challenging and promising field.

Background: The incidence of renal cell carcinoma (RCC), one of the most common malignant tumors in Germany, continues to increase. Medical treatment is indicated in relapsed or metastatic disease., Materials and Methods: The article is based on the content of the recent guidelines and a selective literature search., Results: The use of the introduction of immune checkpoint inhibitors (ICI) and their combination with tyrosine kinase inhibitors (TKI) in particularly vulnerable patients has fundamentally changed the therapeutic landscape. The median overall survival was thus extended to > 40 months. However, until recently neither targeted nor conventional therapy could be established in (neo)adjuvant therapy. New data show survival benefit for patients at high risk of recurrence on adjuvant therapy with pembrolizumab., Conclusions: Currently only pembrolizumab is approved in adjuvant therapy in Germany. Further studies and a longer follow-up will help us in the future in the classification of therapy with ICI and its combination with TKI in localized RCC., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Inhibition of neo-angiogenesis is a cornerstone of medical treatment in metastatic renal cell carcinoma (mRCC). While 1st line therapies were previously dominated by inhibitors of the vascular endothelial growth factor axis, 2nd line options were less clearly defined. We investigated the role of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in 2nd line treatment of mRCC patients., Methods: Key inclusion criteria were measurable mRCC, ECOG 0-1, IMDC risk: good or intermediate and adequate organ function. Patients who progressed on or were intolerant to bevacizumab + interferon were subject for randomization between TKI and EVE treatment. Cross-over occurred at time of progression during 2nd line treatment. Improvement of 2nd line progression-free survival (PFS) rate (PFR) at 6 months from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, objective response rate (ORR), overall survival (OS), safety, and patient reported outcomes., Results: In 2012-2015, a total of 22 patients were included. The study was stopped for poor accrual. Ten patients (46%) were randomized to receive 2nd line treatment with EVE (n = 5) or axitinib (n = 4)/sunitinib (n = 1). ECOG 0 was recorded in 20% (EVE) and 60% (TKI). Severe adverse events occurred in approx. 60% in each arm. ORR was 1/5 (20%) for TKI and 0/5 (0%) for EVE. PFR at 6 months was 20% in each arm. Median PFS was 3.7 months (EVE) and 2.2 months (TKI) (hazard ratio [HR] 1.0 [95% confidence interval [CI]: 0.26-3.85]). The OS was comparable between arms HR 1.12 (95% CI: 0.27-4.61)., Conclusion: The rapid change of the treatment landscape, the limited use of bevacizumab and interferon in 1st line and the duration of 1st line treatment jeopardized BERAT trial recruitment. The small number of patients is a major limitation of our trial. Our observation indicated the poor prognosis in progressive patients and the limited efficacy of TKI or mTOR inhibitors in 2nd line treatment., (© 2022 S. Karger AG, Basel.)

Cetuximab-based chemoimmunotherapy has been the standard of care for recurrent or metastatic squamous cell carcinoma of the head and neck (r/m SCCHN) for more than a decade. To date, no predictive or prognostic biomarkers have been established to further guide the systemic treatment with cetuximab-based chemoimmunotherapy in r/m SCCHN. Against this background, we retrospectively analyzed clinical and blood-based parameters from 218 r/m SCCHN patients treated with chemoimmunotherapy including cetuximab. Multivariate Cox-regression models were used to assess their prognostic or predictive value. Eastern Co-operative Oncology Group (ECOG) performance status (≥2), older age (≥61.8 years), anemia (hemoglobin <11.80), and increased neutrophil-to-lymphocyte ratio (NLR ≥5.73) were independently and strongly associated with inferior overall survival (OS). To group patients according to risk profiles we established a prognostic clinical score (PCS) that can easily be used in clinical practice. The PCS stratified the cohort into low, intermediate, poor or very poor risk subgroups with median OS times of 23.4, 12.1, 7.5, and 4.0 months, respectively. Patients with low risk PCS had a prolonged progression-free survival (PFS) and increased overall response rate (ORR) under first-line cetuximab-based therapy. Interestingly, only patients with low and intermediate risk benefitted from the more intensive first-line cisplatin/cetuximab combination compared to carboplatin/cetuximab therapy, whereas the intensity of first-line treatment had no impact in the poor and very poor risk subgroups. Following external validation, particularly in the context of newly established first-line options, the PCS may guide clinical decision making and serve for stratification of patients with r/m SCCHN in future clinical trials., Competing Interests: MSc: Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Lilly, Novartis; Honoraria for CME presentations: Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis; Research funding to institution: Boehringer Ingelheim, Bristol Myers-Squibb, Novartis; Other: Universität Duisburg-Essen (Patents). SK: Consultancy, Honoraria and Travel Support: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Merck Serono, Sanofi Aventis, Astra Zeneca, Janssen Pharmaceuticals, Celgene, Lilly, Servier. MP: Consultancy, Honoraria and Travel Support: Boehringer Ingelheim, Bristol Myers-Squibb, Merck Healthcare KGaA, Merck Sharp & Dohme. TG: Consultancy, Honoraria and Travel Support: Astra Zeneca, Bristol Myers-Squibb, Merck Healthcare KGaA, Merck Sharp & Dohme, Roche. VG: grants, personal fees and non-financial support from Astra Zeneca, Bristol-Myers Squibb, Ipsen, Pfizer; grants and personal fees from Novartis, personal fees from Eisai, EUSAPharm, Roche, Janssen-Cilag, Merck Serono, MSD Sharp & Dohme, Lilly, PharmaMar, Asklepios Clinic, Clinic of Oldenburg, Diakonie Clinic, Dortmund Hospital, and Onkowissen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pogorzelski, Hilser, Ting, Kansy, Gauler, Stuschke, Schmid, Lang, Grünwald, Schuler and Kasper.)