BACKGROUND:Papillary renal cell cancer (pRCC) represents the largest subgroup within non-clear cell (ncc) RCC. Compared with clear cell RCC (ccRCC), pRCC is considered less sensitive to currently available systemic therapies. Here, we report exploratory results from the pRCC subgroup of the SUNNIFORECAST trial comparing ipilimumab/nivolumab with standard of care (SOC) based on central pathological review. METHODS AND PATIENTS:SUNNIFORECAST was a prospective, investigator-initiated, phase II trial evaluating ipilimumab/nivolumab versus SOC in patients with untreated, advanced nccRCC. The primary endpoint was the 12-month overall survival (OS) rate. Secondary endpoints included OS, progression-free survival (PFS), and overall response rate (ORR). PD-L1 expression was assessed exploratory. RESULTS:Of 309 randomized patients, 127 had confirmed papillary histology, in 56/173 cases the local diagnosis of pRCC required revision. Among the 127 patients with pRCC, 64 received ipilimumab/nivolumab and 63 SOC, predominantly TKI monotherapy. In the pRCC subgroup, the 12-month OS rate was 74.77% in the ipilimumab/nivolumab arm and 63.44% in the SOC arm (p = 0.085). Median OS was 24.89 months with ipilimumab/nivolumab versus 18.88 months with SOC. PD-L1 expression was evaluable in 116 of 127 patients. A CPS > 1 was more frequently observed with increasing IMDC risk category. Among patients with CPS < 1, the 12-month OS rate was 75.00% with ipilimumab/nivolumab and 68.36% with SOC (p = 0.963). In patients with CPS > 1, the 12-month OS rate was 82.38% in the ipilimumab/nivolumab arm and 63.33% in the SOC arm. DISCUSSION:This exploratory analysis has several limitations; however, it suggests that patients with pRCC treated with ipilimumab/nivolumab may derive a benefit in terms of 12-month OS rate, median OS, and ORR compared with SOC, particularly among those with CPS > 1. (Funded by Bristol Myers Squibb grant CA209-499; ClinicalTrials.gov, EUDRACT Number: 2016-000706-12; NCT03075423.).

Background/Objectives: Nivolumab monotherapy is a standard of care in previously treated advanced renal cell carcinoma (aRCC) and was approved based on the results of the randomized clinical trial Checkmate-025. The non-interventional study (NIS) NORA collected data on the effectiveness and safety of nivolumab monotherapy in real-world clinical routine. Its final, long-term follow-up data are presented here. Methods: NORA was a prospective, multicentre NIS recruiting at 54 German sites, evaluating the effectiveness and safety of nivolumab monotherapy in pre-treated patients with aRCC. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), safety, and patient-reported outcomes (PROs). Results: A total of 232 patients were eligible. Of the patients, 15% had favourable, 58% had intermediate, and 15% had poor risk according to the International Metastatic RCC Database Consortium. Of the patients, 77% received nivolumab as second-line, 15% as third-line, and 8% as ≥fourth-line therapy. With a median long-term follow-up of 76 months (minimum 62 months), median OS was 22.2 months (95% confidence interval [CI] 16.5-25.9) and median PFS was 4.1 months (95% CI 3.2-5.4). The ORR was 21% with a median DOR of 27.9 months (95% CI 15.9-not evaluable). Of the patients, 47% and 16% had treatment-related adverse events of all grades and of grades 3-4, respectively. One patient died from autoimmune hepatitis related to treatment. PROs did not reveal any new signals. Conclusions: The long-term follow-up of NORA confirms that nivolumab monotherapy is an effective and safe therapy in patients with aRCC after prior therapy. With comparable follow-up times, our real-world data were not substantially different from the final long-term results of the pivotal Checkmate-025 study.

BACKGROUND:Treatment options after PD-1 inhibition for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) remain limited. We investigated whether staggered immune checkpoint inhibition could improve outcomes compared with docetaxel in nivolumab-refractory disease. METHODS:In this randomized phase II trial, adults with platinum-refractory R/M-SCCHN received nivolumab and were randomized at progression to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (NIVO-IPI) or docetaxel 75 mg/m² every 3 weeks (DOCE) until progression or intolerance. The primary endpoint was objective response rate (ORR) per RECIST 1.1; progression-free survival (PFS), overall survival (OS), and safety were secondary endpoints. PD-L1 expression was assessed in all patients. RESULTS:Among 14 patients in the NIVO-IPI arm and 17 in the DOCE arm, ORR was 0% versus 17.6%, median PFS was 1.97 versus 3.66 months (P = 0.036), and median OS was 3.97 versus 11.9 months (P = 0.356), respectively. Twelve-month OS rates were 28.6% and 44.6%. Outcomes were similar irrespective of PD-L1 status. Treatment-emergent adverse events occurred in 84.6% versus 81.3% of patients, with grade ≥3 events in 38.5% and 68.8%. CONCLUSIONS:NIVO-IPI did not improve efficacy over docetaxel and showed numerically inferior survival, whereas docetaxel was associated with greater toxicity. CLINICAL TRIAL REGISTRATION:EudraCT Nr. 2017-003349-14.

Trabectedin is standard for r/r soft tissue sarcomas. tTF-NGR accumulates in tumor vasculature leading to tumor vascular occlusion and tumor infarction. Both compounds in sequence could trap trabectedin inside tumors and increase its efficacy, which then optimizes the pro-coagulatory activity of tTF-NGR. This report summarizes translational data and results of the safety run-in patient cohort of the TRABTRAP trial combining trabectedin plus tTF-NGR. A dose of trabectedin of 1.5 mg/m2 (24 h, day 1) combined with 1.0 mg/m2 of tTF-NGR (1 h, days 2 and 3, q day 22) represents the approx. Maximum tolerated dose (MTD) and with 0.5 mg/m2 tTF-NGR (days 2 and 3) the recommended starting dose for the randomized part of TRABTRAP. None of the 6 patients on 0.5 mg/m2 tTF-NGR had dose-limiting toxicity (DLT). Higher doses or additional days of application of tTF-NGR led to grade 3 DLT including early troponin T high sensitivity increase, a reversible non-ST-elevation myocardial infarction in one patient, and reversible thromboembolic events. Pharmacokinetics explain the difference of the MTD between the phase I study and in TRABTRAP. Experimental and clinical efficacy and tolerability of the combination between trabectedin and tTF-NGR supports the active randomized part of TRABTRAP.

Zusammenfassung Im Juli 2025 wurde in Deutschland die perioperative Therapie mit Durvalumab in Kombination mit einer neoadjuvanten Gemcitabin-/Cisplatin-basierten Chemotherapie und anschließender radikaler Zystektomie zur Behandlung des muskelinvasiven Blasenkarzinoms zugelassen. Die Zulassung basiert auf der Phase-III-Studie NIAGARA, in der gezeigt werden konnte, dass die Kombinationstherapie im Vergleich zur alleinigen neoadjuvanten Chemotherapie zu einer signifikanten Verbesserung des ereignisfreien Überlebens führte. Zudem war die Rate kompletter pathologischer Remissionen unter Hinzunahme von perioperativem Durvalumab erhöht. Dieser Vorteil spiegelte sich auch im Gesamtüberleben wider, welches unter Kombinationstherapie mit Durvalumab signifikant verlängert war. Dabei wurden weder die Durchführungsrate der Zystektomie beeinträchtigt noch deren Komplikationsrate erhöht. Ziel dieser Arbeit ist es, das perioperative Therapieregime mit Durvalumab im Kontext der verfügbaren Evidenz darzustellen und dessen klinischen Nutzen sowie Limitationen kritisch zu diskutieren. Ein besonderer Fokus liegt auf der Definition geeigneter Kriterien zur Patientenselektion sowie auf der Charakterisierung des Sicherheitsprofils. Dabei werden insbesondere therapieassoziierte schwerwiegende unerwünschte Ereignisse der Grade 3–4 berücksichtigt, wie sie in der NIAGARA-Studie berichtet wurden, darunter Anämie (14% im Durvalumab-Arm), Neutropenie (14%), Harnwegsinfektionen (14%) sowie eine verminderte Neutrophilenzahl (7%). Der Stellenwert von zirkulierender DNA (ctDNA) als prognostischer Marker wird herausgearbeitet, ohne jedoch die Indikation zur radikalen Zystektomie oder zur adjuvanten Therapie infrage zu stellen. Nicht zuletzt gibt der Artikel einen Ausblick zu neuen perioperativen Therapiekonzepten mit dem Antikörper-Wirkstoff-Konjugat Enfortumab Vedotin und Pembrolizumab beim muskelinvasiven Blasenkarzinom.

Abstract:Since July 2025, perioperative durvalumab combined with neoadjuvant gemcitabine/cisplatin chemotherapy followed by radical cystectomy has been approved in Germany for the treatment of muscle-invasive bladder cancer. This approval was based on the phase III NIAGARA trial, which demonstrated that the combination led to a significant improvement in event-free survival compared with neoadjuvant chemotherapy alone. Furthermore, the rate of complete pathological responses was higher with the addition of perioperative durvalumab to neoadjuvant chemotherapy. This benefit was also reflected in overall survival, which was significantly prolonged in the durvalumab combination arm. Importantly, the combination did not compromise the completion rate of cystectomy or increase surgical complication rates. This article aims to present the perioperative durvalumab-based treatment regimen in the context of the available evidence and to critically discuss its clinical benefit and limitations. A particular focus is placed on defining appropriate criteria for patient selection and characterizing the safety profile. In this context, therapy-related grade 3-4 adverse events reported in the NIAGARA trial are specifically considered, including anemia (14% in the durvalumab arm), neutropenia (14%), urinary tract infections (14%), and decreased neutrophil counts (7%). The potential role of circulating tumor DNA (ctDNA) as a prognostic biomarker is also addressed, without questioning the indication for radical cystectomy or adjuvant therapy. Finally, the article provides an outlook on novel perioperative therapeutic concepts involving the antibody-drug conjugate enfortumab vedotin and pembrolizumab for muscle-invasive bladder cancer.

Objectives:Since 2011, immune checkpoint inhibitors (ICI) have transformed the treatment of various cancers. However, our understanding of the autoimmune adverse events, particularly those affecting the nervous system, remains limited. These adverse events can cause significant disability or even death, yet there are currently no established guidelines or biomarkers to aid diagnosis and treatment. With this study, we aim to gain a deeper understanding of neurological adverse events and investigate potential predictive biomarkers. Methods:Between 19 December 2019 and 21 August 2021, 150 out of 543 ICI-treated cancer patients were eligible for our prospective monocentric cohort study. Neurological assessments, clinical scores and the severity of side effects were analysed. Blood samples were taken before, during and after therapy. Patients with neurological AEs (the nAE group) and those without (the non-nAE group) were compared to identify potential predictive markers. Results:Of the 150 patients, 55 (36.7%) experienced nAE of any kind or severity, ranging from non-specific neurological symptoms to severe events. Severe nAE (Grade ≥ 3) was observed in 3.3% of patients and included cases of encephalitis and cerebral vasculitis. Regarding potential biomarkers, an increase in C-reactive protein (CRP) within the first 3-4 weeks was statistically associated with an increased likelihood of nAE in this study. As for patient- and treatment-related parameters, concurrent chemotherapy was found to be significantly associated with the occurrence of nAE. Conclusions:This study observed a relatively high rate of nAE under ICI therapy, partly due to the intentionally broad case definition. CRP elevation emerged as a potential predictive biomarker, warranting further investigation. However, other statistically significant markers did not consistently demonstrate clinical relevance.

BACKGROUND/AIM:In soft-tissue sarcoma (STS) of the extremities, radiotherapy (RT) is known to improve local control, overall survival (OS) and preserve extremity function. Whether RT should be applied pre- or postoperatively is still commonly discussed. This study aimed to gather data about the treatment reality at a certified sarcoma centre and investigate the impact of RT timing on local control, OS and progression-free survival (PFS). PATIENTS AND METHODS:This was a retrospective analysis of all patients who received curative RT for STS of the extremities between 2012 and 2022. Patients were identified using the ICD-10 diagnosis codes C49.1, C49.2 and C49.9. Patient-specific data, such as sex and relevant medical history, were collected. Tumour-specific data included histological subtype, staging, grading and location of the tumour. Therapy-specific data included the type and number of operations, postoperative complications, chemotherapy, RT, and acute and long-term toxicities. All cases were discussed pre-therapeutically in an entity-specific Interdisciplinary Tumour Board. RESULTS:A total of 67 patients were included; 49 who received adjuvant RT were compared to 18 that received neoadjuvant RT. Mean follow-up was 17.83 months for the neoadjuvant RT cohort and 21.29 months for the adjuvant RT cohort. PFS for the neoadjuvant RT cohort averaged 25.7 months (range=5.2-52.7 months) compared to 15.1 months for the adjuvant RT cohort (range=0.8-51.1 months) (p=0.162). At 2 years, OS rates were 95.9% for patients treated with adjuvant RT and 94.4% for the neoadjuvant RT group. CONCLUSION:STS is a heterogeneous and rare oncological entity and clear data on subtype-adapted therapy are still lacking. This study highlights the complexity and the influence of various factors on the choice of treatment approach and outcome, suggesting that neoadjuvant RT may be beneficial.

Molecular tumor boards (MTBs) support precision oncology by translating genomic profiling into evidence-based treatment recommendations, for example according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT). Their clinical utility in real-world care depends on effective implementation within healthcare systems. To evaluate the implementation rate of MTB recommendations, associated determinants, and clinical outcomes in a real-world single-center cohort. At a single-center MTB, 582 consecutive cases (2020–2023) were retrospectively analyzed, with last survival follow-up in August 2025. Patient demographics, tumor characteristics, genomic alterations, ESCAT and ZPM (Zentrum für Personalisierte Medizin) evidence levels, targeted therapy recommendation and implementation rates, survival outcomes, and barriers to implementation were evaluated using descriptive and inferential statistics, as appropriate. Of 582 patients (median age 61 years, 48.5

INTRODUCTION:Therapies using immune checkpoint inhibitors (ICI) are standard of care in metastatic renal cell carcinoma (mRCC). Currently, no accepted standardized biomarkers are available to predict treatment response in mRCC. We aimed to identify the predictive value of immunomodulatory markers interacting within the tumor microenvironment. PATIENTS AND METHODS:We included 45 untreated and pretreated patients treated with ICI, divided by their progression free survival (PFS) into groups of good (> 18 months), intermediate (6-18 months) or poor treatment response (< 6 months). Tumor specimens were stained immunohistochemically for 28 markers and analysed by application of digital tissue microarrays using the open source software QuPath. RESULTS:The phagocytosis checkpoint molecule CD47 significantly predicted and higher CD20 (B cell density) was significantly correlated with longer PFS. CD20 was associated with tumor-infiltrating immune cells and checkpoint molecules. CONCLUSIONS:Tissue based quantification of CD47 and CD20 might be used to predict response to ICI in mRCC. Both markers influence the anti-tumor response and seem to be markers of a highly immune-infiltrated, and simultaneously functional immunosuppressed TME which seem to profit the most from ICI. Therefore, CD47 and CD20 could be suitable to discriminate between patients which profit from those who would not profit from ICI and avoid unnecessary costs due to side effects.

BACKGROUND:Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined subgroup of non-clear cell RCC (nccRCC) lacking an approved standard treatment. We report the exploratory analysis of this entity within the SUNNIFORECAST trial. METHODS:SUNNIFORECAST evaluated ipilimumab/nivolumab versus standard of care (SOC) in previously untreated, advanced nccRCC. The primary endpoint was the 12-months overall survival (OS) rate. Secondary endpoints included median OS, progression free survival (PFS) and overall response rate (ORR). PD-L1 expression was assessed exploratorily. RESULTS:Of 309 randomized patients, 30 had centrally confirmed FH-deficient RCC (ipilimumab/nivolumab, n=14; SOC, n= 16). The 12-months OS rate was 85.7% (95% confidence interval [CI] 53.9-96.2%) versus 73.3% (95% CI 43.6-89.1%), median OS was 35.7 months (95% CI 16.8 months-NE) versus 24.7 months (95% CI 10.6-37.7 months, hazard ratio [HR] 0.46 [0.17-1.20]), and ORR 42.9% versus 33.3%, favoring ipilimumab/nivolumab. Twenty-four patients were evaluable for PD-L1 expression; 21 had a combined positive score (CPS) ≥1. In this subgroup, the 12-months OS rate was 80.0% (95% CI 40.9-94.6%) versus 72.7% (95% CI 37.1-90.3%), median OS 38.3 months (95% CI 8.8 months-NE) versus 24.7 months (95% CI 8.8 months-NE, HR 0.43 [0.14-1.34]) and ORR 40.0% versus 36.4% for ipilimumab/nivolumab versus SOC, respectively. INTERPRETATION / DISCUSSION:Exploratory analyses suggest trends toward improved 12-months OS-rate, median OS and ORR with ipilimumab/nivolumab versus SOC in FH-deficient RCC. The majority of tumors demonstrated PD-L1-expression (e.g. CPS ≥ 1), warranting further investigation in prospective studies.

Introduction: The introduction of immune checkpoint inhibitors (CPIs) in oncology has improved the long-term perspectives of many patients and is bringing the quality of life (QoL) into focus as a treatment-relevant variable. In clinical routine, standardized and reliable tools for collecting, understanding, and utilizing QoL information are needed. In the current work, an interdisciplinary consensus on aspects of QoL in standard clinical practice has been put forth. METHODS:After independent, structured individual interviews with members of an interdisciplinary expert panel (n = 12), ten theses on QoL with particular consideration regarding CPI therapy were drafted. These formed the basis of a multistage, independent, anonymous, externally commented, qualitative Delphi process. During the period May - December 2022, the panel developed interdisciplinary consensus recommendations for recording QoL and its role in decision-making in everyday care. RESULTS:Out of ten theses, five recommendations arranged into three subject areas were agreed upon. QoL is considered a multifactorial and dynamic parameter that goes far beyond treatment-associated side effects. Mindful communication with the patient is considered the basis for QoL assessment and QoL modification. In everyday clinical practice, QoL should be documented and assessed in a structured, regular, and individualized way, thereby providing a basis for decisions on treatment options. CONCLUSION:The individual QoL of cancer patients should be assessed before and throughout therapy. Especially for long-term responders of CPI therapy and in the adjuvant setting, QoL appears to be treatment relevant. The recommendations based on the Delphi method provide practical assistance. .

523 Background: Tyrosine kinase (TKI) and immune checkpoint inhibitors (CPI) are first-line options in metastatic renal cell carcinoma (mRCC). Most patients (pts) experience adverse events (AE) and 20-30% discontinue therapies due to AEs. We tested whether proactive onco-coaching (POC) improved quality of life (QoL) in patients with medical treatment. Methods: Adult treatment-naïve mRCC pts who were candidates for sunitinib (SU), axitinib + avelumab (AA) or axitinib + pembrolizumab (AP) were eligible. Treatment and modifications were at the physician's discretion. Pts were 1:1 randomized to POC by a trained nurse (8 visits of structured interviews educating on preventive, preemptive and supportive measures, and phone call follow-up for a total of 24 wks) or standard of care (SOC). Primary endpoint was the fraction of pts with QoL improvement (QOLI) by ≥3 points (minimal important difference: MID) of the FKSI-15 score. Secondary endpoints consisted of patient reported outcomes (PRO: FACT-G, EQ-5D), time to QOLI, efficacy, survival and safety (CTCTAE 4.03). The planned sample size was 430 pts. Log rank analyses were employed for time to event endpoints and Fisher exact tests for categorical data. Results: Between 2016 and 2023, 113 pts were included. Median age was 72 and 68y (POC vs. SOC). 44% had a Charlson Comorbidity Index (CCI) ≥2. MSKCC good/intermediate/poor risk were 21/61/12%. 86% had clear cell histology. Of 110 treated patients, 39% and 61% received SU or AXI-CPI (AA or AP). FKSI-15-completion rate was 85%. 80 pts (73%) had ≥2 PRO assessments and were evaluable for the primary endpoint. There was no difference in QOLI between POC and SOC (43.6% vs. 41.5%; p=0.95). Mean baseline FKSI-15 score was similar between arms, as were ORR (38.2 [95% CI 25.4-52.3] vs. 34.5% [95% CI 22.2-48.6]; p=0.96) and PFS (11.1 [95% CI 8.3- 18.9] vs. 9.2 mo [95% CI 5.6-14.6]; p=0.21). Overall survival was favored by POC (median 49.6 [95% CI 30.6- 61.6] vs. 25.4 mo [95% CI 17.8-NC]; p=0.11). Stratification by CCI had no relevant effect on OS in the POC arm (p=0.26), while pts. with CCI ≥2 had poorest OS in the SOC arm (15.7 vs. 33.4 mo; p=0.002). Treatment related AEs of any or ≥3 grade affected 96.4% and 52.7% with POC and 85.5% and 36.4% with SOC. Discontinuation due to toxicity between POC vs. SOC occurred for TKI in 7.3 vs. 9.1% and for CPI in 18.2 vs. 5.5% pts. Conclusions: Target patient accrual was not reached, and POC did not improve the rate of QoL responders or treatment efficacy. However, there was a trend towards a considerable extension of OS in the POC group, suggesting an overall beneficial impact of proactive coaching compared to standard reactive therapy management. Comorbid patients putatively benefit most from pro-active coaching, which warrants further studies. Clinical trial information: NCT03013946 .