BACKGROUND AND PURPOSE:Patients with renal cell carcinoma (RCC) in a solitary kidney have limited treatment options. Stereotactic MRI-guided adaptive radiotherapy (SMART) offers a non-invasive alternative that preserves healthy kidney tissue. This study evaluated the clinical outcomes of SMART in patients with renal tumors in a solitary kidney. Oncological outcomes, renal function preservation, and treatment-related toxicity were assessed. MATERIALS AND METHODS:All consecutive patients with RCC in a solitary kidney treated with SMART between 2018 and 2024 in a single center were analyzed. Local control was defined as any response or stable disease using RECIST criteria. Kaplan-Meier analysis was used for survival outcomes and paired t-tests assessed renal function changes. RESULTS:Thirty-two patients with a median age of 70 years were included. Most patients had WHO status 0-1 (93.8%) and had prior nephrectomy for RCC (78.1%). Median tumor size was 4.2 cm, and median pre-treatment eGFR was 45.8 ml/min. Seven patients were treated for multiple lesions, in simultaneous or separate sessions. Most patients were treated in a single (22.8%) or five (74.3%) fractions. After a median follow-up of 21.3 months, the local control rates at 1 and 2 years were 96.2% and 90.1%, respectively. Mean eGFR change was -6.6 ml/min, none required dialysis. No grade ≥ 3 toxicity was observed. The overall survival rate at 2 years was 80.9%. CONCLUSION:SMART provides high local control with minimal impact on renal function, offering a non-invasive, kidney-sparing treatment option that also enables repeated treatments within the solitary kidney.

To assess tumour factors that reduce primary technical efficacy (PTE) from CT-guided renal cryoablation. Patients were taken from the EuRECA registry between December 2014 and November 2020. To focus on tumour factors rather than individual technique, this study was limited to cases using CT and excluded procedures using cone beam, US, MRI, or laparoscopy. PTE was assessed per tumour and defined as complete ablation of the target on enhanced CT or MRI by 90 days. Residual unablated tumour (RUT) was defined as focal persistent tumour enhancement within 90 days. A total of 1,424 tumours from 11 different centres were eligible; 38 episodes of RUT were detected giving an overall PTE of 97.3

Stage 1 (cT1) renal cell carcinoma (RCC) can be treated by cone-beam CT-guided percutaneous cryoablation (CBCT-guided PCA). The RENAL nephrometry scoring system provides a structured method for evaluating the complexity of renal tumours by classifying them based on specific anatomical features. The aim was to evaluate the clinical utility of this scoring system in predicting postoperative oncological and functional outcomes in patients undergoing CBCT-guided PCA as their primary treatment for biopsy proven cT1 RCC. 91 patients were retrospectively analyzed. A statistically significant association was found between the RENAL nephrometry score classification and local treatment failure (p = 0.005). The RENAL score was not found to correlate with local tumour recurrence, postoperative complications, or change in renal function. These findings suggest that the RENAL nephrometry score can be utilized for risk stratification and more precise patient counseling.

4509 Background: NEOAVAX (NCT03341845) is an open label, single arm, phase II trial, investigating 12 weeks of neoadjuvant avelumab/axitinib prior to nephrectomy in 40 pts with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4 cN0-1 M0, Grades 3-4). Dynamic on-treatment increase of CD8+ tumor infiltrating lymphocytes (TILs) in the tumour microenvironment (TME) and the primary endpoint (radiographic partial response rate (RECIST 1.1) in the primary tumour (PT) in ≥25%) were reported previously together with safety and tolerability [1]. Methods: Exploratory analysis included pathologic response in the PT according to the International Neoadjuvant Melanoma Consortium (INMC) and multiplex immune histochemistry (IHC) of the TME including CD8+, CD8-granzyme-B+, CD8+CD39+, Foxp3+ cells and MHC-I in paired samples (pre-treatment biopsy and nephrectomy) from 40 pts;. IHC data were compared to RECIST 1.1 and pathologic response in the PT, and recurrence; Visium spatial transcriptomics was performed on 18 PT from pts with diverging clinical outcome. Results: The majority of pts (n=25 (62.5%) had no pathologic response (pNR) by INMC criteria. Twelve patients (30%) had a partial (pPR) and 3 (7.5%) a major pathological response (MPR). There was no association between pathological and radiographic response of the PT. Recurrence occurred in 1 of 3 pts (33%) with MPR at 36 mo, in 7 of 12 (58%) with a pPR at a median of 12 mo and in 14 of 25 (56%) with pNR at a median of 3 mo. Of 25 pts with pNR 7 died of disease (DoD; 28%). On IHC, intratumoural CD8+CD39+ on post-treatment PT samples was significantly associated with recurrence (p<0.0001). MPR associated with spatial co-localisation of tumour cells with tissue-resident macrophages, CD8+ cytotoxic T-cells, memory T-cells and B-cells. Gene Set Enrichment Analysis (GSEA) results for Reactome pathways in each Visium tumor spot cluster demonstrated intratumoural heterogeneity in post-treatment PT in select patients. Conclusions: Pathologic response and IHC post-treatment influx of CD8+CD39+ TILs associates with prolonged disease-free survival following neoadjuvant avelumab/axitinib. Particularly, pts with MPR had distinct spatial co-localisation gene signatures of tumour and immune cells in the TME. Despite 3 months of treatment, 62.5% of pts had no pathologic responses (defined by INMC as >50% vital tumour remaining in the tumour bed). [1] Bex A et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx), in 2022 ASCO Genitourinary Cancers Symposium . Journal of Clinical Oncology, Volume 40, Number 6_suppl, https://doi.org/10.1200/JCO.2022.40.6_suppl.2. Clinical trial information: NCT03341845 .

Purpose Treatment of renal cell carcinoma (RCC) in patients with solitary kidneys remains challenging. The purpose of this multicentre cohort study was to explore how renal function is affected by percutaneous image-guided cryoablation in patients with solitary kidneys. Material and Methods Data from the European Registry for Renal Cryoablation database were extracted on patients with RCC in solitary kidneys treated with image-guided, percutaneous cryoablation. Patients were excluded if they had multiple tumours, had received previous treatment of the tumour, or were treated with more than one cryoablation procedure. Pre- and post-treatment eGFR (within 3 months of the procedure) were compared. Results Of 222 patients with solitary kidneys entered into the database, a total of 70 patients met inclusion criteria. The mean baseline eGFR was 55.8 ± 16.8 mL/min/1.73 m 2 , and the mean 3-month post-operative eGFR was 49.6 ± 16.5 mL/min/1.73 m 2 . Mean eGFR reduction was − 6.2 mL/min/1.73 m 2 corresponding to 11.1% ( p = 0.01). No patients changed chronic kidney disease group to severe or end-stage chronic kidney disease (stage IV or V). No patients required post-procedure dialysis. Conclusion Image-guided renal cryoablation appears to be safe and effective for renal function preservation in patients with RCC in a solitary kidney. Following cryoablation, all patients had preservation of renal function without the need for dialysis or progression in chronic kidney disease stage despite the statistically significant reduction in eGFR. Level of Evidence 3 Observational study. Graphical Abstract

ObjectiveTo describe the impact of a multidisciplinary tumor board (MTB) for renal cell carcinoma (RCC) patients in a locoregional renal cancer network by evaluating shared decision making (SDM) and adherence to MTB recommendations.Design, Setting and ParticipantsThis prospective cohort study included all cases from a Dutch renal cancer network with suspicion of or histologically confirmed RCC discussed in MTBs between 2017-2022. Main endpoints were distribution of cases presented, proportion of recommendations with multiple treatment options enabling shared decision making (SDM), definite treatment after SDM and adherence to MTB recommendations. Further endpoints were definite treatment per tumor stage stratified by age and inclusion in clinical trials. Outcomes were displayed as means and proportions (%). Pearson's Chi-Squared test was used to analyze the effect of age on definite treatment advice.ResultsOverall, 2651 cases were discussed, of which 1900 (72%) were new referrals and 751 (28%) rediscussions. Majority of cases were cT1a-b tumors (46%) and 22% were local recurrences or metachronous metastatic. Adherence to MTB recommendation was 96% and in 30% multiple treatment options were recommended, allowing for SDM. In 45% of cases with cT1a tumors multiple treatment options were recommended by the MTB, resulting in (cryo)ablation (32%) and AS (30%) as most frequent definite treatments after SDM. Among patients with cT3-4 tumors the inclusion rate in clinical trials was 47%.ConclusionsA network MTB creates opportunity to discuss multiple treatment options and clinical trials in SDM with patients at a high rate of adherence to MTB recommendation.

Objectives: To determine the rate of benign pathology in cT1 tumors following partial nephrectomy in the Netherlands, thereby evaluating the rate of overtreatment. Methods: Data were collected from a nationwide database containing histopathology of resected renal tissue from 2014 to 2022. Patients who underwent partial nephrectomy for suspected RCC staged T1a-b were extracted for analysis. Data are shown in percentages, and multivariable logistic regression was performed to determine predictive factors for benign pathology. Results: 3409 cases were analyzed, of which 403 (12%) were benign and 3006 (88%) malignant. Subtype analysis showed 2126 (62%) cases of clear-cell RCC, followed by 604 (18%) of papillary RCC and 344 (10%) oncocytomas. Mean age was 63 years among patients with malignant pathology versus 65 years for patients with benign lesions (p < 0.001). Mean tumor size was 3.2 cm for malignant pathology and 2.9 cm for benign (p < 0.001). The rates of benign and malignant pathology did not change between 2014 and 2022 (p = 0.377). Multivariable regression showed age ≥ 65 years (65–79 years [OR 1.881, p = 0.002], ≥ 80 years [OR 3.642, p < 0.001]) and tumor size (OR 0.793, p < 0.001) as predictors for benign pathology. The main limitation of this study is that we do not know the biopsy rate of our cohort. Conclusion: This study reports a low rate of 12% benign pathology after partial nephrectomy in the Netherlands. It remains debatable whether these rates are acceptable, or if renal tumor biopsies should be utilized more frequently to reduce overtreatment.

This study aims to evaluate the safety, efficacy, and renal function preservation of percutaneous cryoablation (PCA) for small renal masses (SRMs) in inherited RCC syndromes. Patients with inherited T1N0M0 RCCs (<7 cm) undergoing PCA from 2015 to 2021 were identified from the European Registry for Renal Cryoablation (EuRECA). The primary outcome was local recurrence-free survival (LRFS). The secondary outcomes included technical success, peri-operative outcomes, and other oncological outcomes estimated using the Kaplan–Meier method. Simple proportions, chi-squared tests, and t-tests were used to analyse the peri-operative outcomes. A total of 68 sessions of PCA were performed in 53 patients with RCC and 85 tumours were followed-up for a mean duration of 30.4 months (SD ± 22.0). The overall technical success rate was 99%. The major post-operative complication rate was 1.7%. In total, 7.4% (2/27) of patients had >25% reduction in renal function. All oncological events were observed in VHL patients. Estimated 5-year LRFS, metastasis-free survival, cancer-specific survival, and overall survival were 96.0% (95% CI 75–99%), 96.4% (95% CI 77–99%), 90.9% (95% CI 51–99%), and 90.9% (95% CI 51–99%), respectively. PCA of RCCs for patients with hereditary RCC SRMs appears to be safe, offers low complication rates, preserves renal function, and achieves good oncological outcomes.

Objectives To describe the prostate cancer (PCa) detection rate, including clinically significant prostate cancer (csPCa), in a large cohort of patients who underwent transperineal ultrasonography‐guided systematic prostate biopsy (TPB‐US) using a probe‐mounted transperineal access system, with magnetic resonance imaging (MRI) cognitive fusion in case of a Prostate Imaging–Reporting and Data System grade 3–5 lesion, under local anaesthesia in an outpatient setting. Additionally, to compare the incidence of procedure‐related complications with a cohort of patients undergoing transrectal ultrasonography‐guided (TRB‐US) and transrectal MRI‐guided biopsies (TRB‐MRI). Patients and Methods This was an observational cohort study in men who underwent TPB‐US prostate biopsy in a large teaching hospital. For each participant, prostate‐specific antigen level, clinical tumour stage, prostate volume, MRI parameters, number of (targeted) prostate biopsies, biopsy International Society of Uropathology (ISUP) grade and procedure‐related complications were assessed. csPCa was defined as ISUP grade ≥2. Antibiotic prophylaxis was only given in those with an increased risk of urinary tract infection. Results A total of 1288 TPB‐US procedures were evaluated. The overall detection rate for PCa in biopsy‐naive patients was 73%, and for csPCa it was 63%. The incidence of hospitalization was 1% in TPB‐US (13/1288), compared to 4% in TRB‐US (8/214) and 3% in TRB‐MRI (7/219; P = 0.002). Conclusions Contemporary combined systematic and target TPB‐US with MRI cognitive fusion is easy to perform in an outpatient setting, with a high detection rate of csPCa and a low incidence of procedure‐related complications.

Background:Updating evidence-based clinical practice guidelines is an onerous process and there is a call for more efficient determination of key questions that need updating. Especially for surgical techniques it is unclear if new evidence will result in substantial changes after wide implementation and if continuous updating is always necessary.Objectives:This study analyses the impact of updating a surgical guideline and proposes suggestions for optimising this process.Materials and methods:The Dutch Minimally Invasive Surgery guideline was developed in 2011 and updated in 2021. For both versions a multidisciplinary guideline working group (GDG) was created, that determined key questions. Changes in conclusions and recommendations were analysed by the GDG and statements for expected change of recommendations in the future were made.Results:15 key questions were formed, of which 12 were updates of the previous guideline. For only 27% of the updated key questions, the conclusions changed. In ten years, the body grew only marginally for most key questions and quality of the evidence did not improve substantially for almost all key questions. However, in this first update of the MIC guideline, many recommendations did change due to a more robust interpretation of the conclusions by the GDG. Based on analysis of this updating process, the GDG expects that only four out of 15 recommendations may change in the future.Conclusion:We propose an additional step at the end of guideline development and updating, where the necessity for updating in the future is determined for each key question by the GDG, using their valuable knowledge gained from developing or updating the guideline. For surgical guidelines, the authors suggest updating key issues if it includes a relatively newly introduced surgical- or adapted technique or a new patient group. Low quality or small body of evidence should not be a reason in itself for updating, as this mostly does not lead to new evidence-based conclusions. This new step is expected to result in a more efficient prioritising of key questions that need updating.What’s new?:By adding one additional step at the end of the updating process, the future updating process could become more efficient.

To show the effect of a 6-month (4 times weekly followed by 5 times monthly) maintenance mitomycin C regimen on the prevention of intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). A total of 119 patients undergoing a RNU between 2007 and 2021 in a single center hospital were retrospectively reviewed. A total of 66 patients were eligible for further analysis. 27 patients received no post-operative MMC (median follow-up: 110 months) and 39 patients received a 6-month (4 times weekly, 5 times monthly) maintenance regimen of MMC (median follow up: 48 months). The primary outcome was the 1-, 2- and 5-year bladder recurrence free survival (BRFS). There was a significant difference (p = 0.001) in BRFS between the two groups. The 1-, 2, and 5-year BRFS for the MMC− group was 67

Objectives:To analyse variation in clinical management of cT1 renal cell carcinoma (RCC) in the Netherlands related to surgical hospital volume (HV). Materials and methods:Patients diagnosed with cT1 RCC during 2014-2020 were identified in the Netherlands Cancer Registry. Patient and tumour characteristics were retrieved. Hospitals performing kidney cancer surgery were categorised by annual HV as low (HV < 25), medium (HV = 25-49) and high (HV > 50). Trends over time in nephron-sparing strategies for cT1a and cT1b were evaluated. Patient, tumour and treatment characteristics of (partial) nephrectomies were compared by HV. Variation in applied treatment was studied by HV. Results:Between 2014 and 2020, 10 964 patients were diagnosed with cT1 RCC. Over time, a clear increase in nephron-sparing management was observed. The majority of cT1a underwent a partial nephrectomy (PN), although less PNs were applied over time (from 48% in 2014 to 41% in 2020). Active surveillance (AS) was increasingly applied (from 18% to 32%). For cT1a, 85% received nephron-sparing management in all HV categories, either with AS, PN or focal therapy (FT). For T1b, radical nephrectomy (RN) remained the most common treatment (from 57% to 50%). Patients in high-volume hospitals underwent more often PN (35%) for T1b compared with medium HV (28%) and low HV (19%). Conclusion:HV is related to variation in the management of cT1 RCC in the Netherlands. The EAU guidelines have recommended PN as preferred treatment for cT1 RCC. In most patients with cT1a, nephron-sparing management was applied in all HV categories, although differences in applied strategy were found and PN was more frequently used in high HV. For T1b, high HV was associated with less appliance of RN, whereas PN was increasingly used. Therefore, closer guideline adherence was found in high-volume hospitals.

Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs). PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a ‘Trial within cohorts’ studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician. Ethical board approval has been obtained (2021_218) and the study has been registered at ClinicalTrials.gov (NCT05326620). PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization.

289 Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a first-line standard of care for metastatic RCC. Neoadjuvant use of these combinations may lead to downstaging and reduce the risk of recurrence. In addition, sequential tissue may allow identification of key immune biomarkers associated with outcome. Methods: Neoavax is a single arm phase II trial of 12 weeks neoadjuvant avelumab/axitinib prior to nephrectomy in 40 pts with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4cN0-1M0, Grades 3-4). Primary endpoint is RECIST 1.1 partial response (PR) in the primary tumour (PT) in ≥25%. Secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD-L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and MHC-I were compared on pre-treatment biopsy and nephrectomy samples from 34 pts (NCT03341845). Results: Pts/tumour characteristics are shown in table. Twelve pts (30%) had a PR of the PT from a baseline mean diameter of 10.3 (range 5.6-16.4) cm. Median PT downsizing was 20 (0-43.5) % and median post-treatment vital tumour presence was 50 (1-100) %. At a median follow-up of 23.5 months, recurrence occurred in 13 (32%) pts at a median of 8 (2-23) months and 3 died of disease. Of the 12 pts with PT PR, 11 (92%) are disease-free. Median DFS and OS are not reached. Postoperative adverse events occurred in 8 pts (2 Clavien Dindo grade 3a). There were no treatment-related surgery delays and no PT progression. Post-treatment samples showed upregulation of PD-L1 expression (p <0.0001) and total CD8+ densities (p < 0.01) when compared to pre-treatment biopsies. Comparing samples of pts with PR vs no PR in the PT, no clear immune marker differences were observed. Post-treatment samples from pts that recurred were characterized by lower densities of total, intra-epithelial and stromal CD8+, intra-epithelial CD8+CD39+ (p<0.05) and total CD8+GZMB+ (p=0.1). Pre-treatment biopsies showed no clear differences. Conclusions: Neoadjuvant avelumab/axitinib for non-metastatic high-risk RCC leads to PR of the PT in 30% which is associated with DFS. Pts without recurrence had a significant increase in CD8+ densities compared to pts with recurrence suggesting expansion of a pre-existing immune response. Clinical trial information: NCT03341845. [Table: see text]

To evaluate the use of pre-cryoablation biopsy for small renal masses (SRMs) and the effects of increasing uptake on histological results of treated SRMs. From 2015 to 2019, patients with sporadic T1N0M0 SRMs undergoing percutaneous, laparoscopic, or open cryoablation from 14 European institutions within the European Registry for Renal Cryoablation (EuRECA) were included for the retrospective analysis. Univariate and multivariate logistic models were used to evaluate the trends, histological results, and the factors influencing use of pre-cryoablation biopsy. In total, 871 patients (median (IQR) age, 69 (14), 298 women) undergoing cryoablation were evaluated. The use of pre-cryoablation biopsy has significantly increased from 42% (65/156) in 2015 to 72% (88/122) in 2019 (p < 0.001). Patients treated for a benign histology are significantly more likely to have presented later in the trend, where pre-cryoablation biopsy is more prevalent (OR: 0.64, 95% CI 0.51–0.81, p < 0.001). Patients treated for undiagnosed histology are also significantly less likely to have presented in 2018 compared to 2016 (OR 0.31, 95% CI 0.10–0.97, p = 0.044). Patients aged 70+ are less likely to be biopsies pre-cryoablation (p < 0.05). R.E.N.A.L. nephrometry score of 10+ and a Charlson Comorbidity Index > 1 are factors associated with lower likelihood to not have received a pre-cryoablation biopsy (p < 0.05). An increased use of pre-cryoablation biopsy was observed and cryoablation patients treated with a benign histology are more likely to have presented in periods where pre-cryoablation biopsy is not as prevalent. Comparative studies are needed to draw definitive conclusions on the effect of pre-cryoablation biopsy on SRM treatments. • The use of biopsy pre-ablation session has increased significantly from 42% of all patients in 2015 to 74% in 2019. • Patients are less likely to be treated for a benign tumour if they presented later in the trend, where pre-cryoablation biopsy is more prevalent, compared to later in the trend (OR 0.64, 95% CI 0.51–0.81, p < 0.001). • Patients with comorbidities or a complex tumour (R.E.N.A.L. nephrometry score > 10) are less likely to not undergo biopsy as a separate session to cryoablation.

Surgery is currently the only curative treatment of locally advanced renal cell carcinoma (RCC). Despite surgical resection, intermediate- to high-risk patients still can develop disease recurrence or systemic progression. These patients may benefit from adjuvant or neoadjuvant treatment options. Based on promising results in metastatic disease, immune checkpoint inhibition could be a good therapeutic strategy for the perioperative setting. Preclinical data and early clinical studies in melanoma suggest a greater efficacy of neoadjuvant immunotherapy compared to the adjuvant approach. This trial was designed to treat RCC patients who are at risk for recurrence or distant metastases with different neoadjuvant immunotherapy combinations to obtain the most efficacious and least toxic treatment option for this setting. This randomized, open-label, three-arm phase 2 trial aims to assess the efficacy and safety of neoadjuvant nivolumab alone or in combination in intermediate- to high-risk non-metastatic clear cell RCC using an adaptive trial design. A maximum number of 69 patients will be randomized to receive either 2 courses nivolumab 360 mg, 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg or 2 courses of nivolumab 360 mg + relatlimab 360 mg every three weeks prior to surgery. The primary endpoint is pathologic response rate defined as the proportion of patients demonstrating a complete or partial pathologic response. Secondary endpoints include safety, objective response rate, recurrence-free survival, event-free survival, rate of distant metastases and local recurrences and surgical morbidity. Blood samples, pretreatment biopsies and post-treatment tumor tissue will be collected for translational research. After 42 patients have been recruited (14 per arm), an interim analysis will be performed to evaluate the observed efficacy and toxicity within each arm and either allow for early discontinuation or continuing recruitment in the second stage of a Simon's two stage design. The first patient was enrolled in April 2022. NCT05148546, Registered December 8, 2021. NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital. Bristol Myers Squibb (BMS).