A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma.

BACKGROUND: Nivolumab plus ipilimumab has demonstrated improved survival for treatment-naïve advanced clear cell renal cell carcinoma (RCC). A series of clinical trials evaluated the effect of salvage nivolumab plus ipilimumab in patients without an objective response to nivolumab. Given the size and heterogeneity of these studies, we performed a pooled analysis to better inform the activity of nivolumab plus ipilimumab after nivolumab. PATIENTS AND METHODS: Eligible patients included those with advanced clear cell RCC having received no prior immunotherapy. The primary objective was confirmed objective response rate (ORR) by investigator-assessment. Secondary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: The analysis included 410 patients with clear cell RCC, of whom 340 (82.9%) had IMDC intermediate/poor risk disease, and 137 (33.4%) had prior treatment. The 16-18-week ORR to nivolumab prior to nivolumab plus ipilimumab was 22.7% (n = 93), and best ORR to nivolumab was 25.1% (n = 103). Two hundred and thirty (56.1%) patients treated with nivolumab received nivolumab plus ipilimumab at a median of 16 weeks (IQR 9-19) after initiation of nivolumab [27.0% (n = 62) with stable disease and 73.0% (n = 168) with progressive disease to nivolumab]. The ORR to nivolumab plus ipilimumab was 12.6% (n = 29). Six-month PFS on nivolumab plus ipilimumab was 37% (95% CI, 27-47). Median follow-up was 34.3 months and 3-year OS was 59% (95% CI, 53-64) from nivolumab start. CONCLUSION: A small subset of patients lacking a response to nivolumab derive benefit from salvage nivolumab plus ipilimumab. When possible, both drugs should be given in concomitantly, rather in an adaptive fashion.

Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.

Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma. METHODS: TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete. FINDINGS: Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5-34·8), 39 (36%, 90% CI 28-44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24-40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3-4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia. INTERPRETATION: In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy. FUNDING: Bristol Myers Squibb.

Reasonability of Frequent Laboratory Analyses during Therapy with Nivolumab and Nivolumab+Ipilimumab in Patients with Advanced or Metastatic Renal Cell Carcinoma during the Phase 2 Clinical Trial TITAN-RCC.

In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab.

Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma: A Nonrandomized Clinical Trial.

Importance: Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective: To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants: In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions: All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures: The primary end point was objective response rate. Results: The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance: In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration: ClinicalTrials.gov Identifier: NCT03219775.

[Combination therapy with poly(adenosine diphosphate-ribose) polymerase (PARPi) and androgen receptor signaling pathway (ARPi) inhibitors for metastatic castration-resistant prostate cancer]. / Kombinationstherapie mit Inhibitoren der Poly(Adenosindiphosphat-Ribose)-Polymerasen (PARPi) und des Androgenrezeptorsignalweges (ARPi) beim metastasierten kastrationsrefraktären Prostatakarzinom.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying clinical and molecular subtypes. Almost one-third of patients have abnormalities in homologous recombinant repair genes. Again, about one third of these mutations affect the BReast CAncer 1 or 2 (BRCA 1 or BRCA 2) genes, which generally render tumours receptive to treatment with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi). In 2020 the PARPi olaparib was approved for the treatment of mCRPC after progression with a new hormonal drug (androgen receptor signaling pathway inhibitors, ARPi). In 2022 and 2023 approval of two combination therapies followed, each combining a PARPi and an ARPi (olaparib plus abiraterone and niraparib plus abiraterone). The combination of talazoparib plus enzalutamide will be approved soon. This article introduces the pivotal clinical trials that led to the approval of the respective substances, reports the side effects that may occur during therapy with PARPi plus ARPi, and offers recommendations for management of these side effects.

[Antibody-drug conjugates as new therapeutic agents in uro-oncology]. / Antikörper-Wirkstoff-Konjugate als neues Wirkprinzip in der Uroonkologie.

Antibody-drug conjugates represent a new class of therapeutic agents that are already being used in the field of uro-oncology. They consist of an antibody directed against a specific tumour antigen linked to a cytotoxic substance ("payload") which acts after internalisation into the tumour cell and its release. Currently, approval in the European Union is restricted to enfortumab vedotin which is directed against nectin­4 and carries the microtubule-inhibiting active ingredient monomethyl auristatin E (MMAE). Enfortumab vedotin is approved for locally advanced or metastatic urothelial carcinoma in the third line of therapy after platinum-based chemotherapy and after therapy with a programmed cell death (ligand) 1 (PD-[L]1) immune checkpoint inhibitor. However, an expansion of the indication of enfortumab vedotin as monotherapy and in combination with PD-(L)1 immune checkpoint inhibitors, as well as approval of other antibody-drug conjugates is expected in the future. This could sustainably change the therapy sequence in urothelial carcinoma. Currently, several clinical trials are recruiting in different therapeutic settings. This article presents the new substance class of antibody-drug conjugates, their mechanism of action, their representatives and clinical studies, and points out practice-relevant side effects and how to deal with them.

BCL-2 modifying factor (BMF) is a central regulator of anoikis in human intestinal epithelial cells.

BCL-2 modifying factor (BMF) is a sentinel considered to register damage at the cytoskeleton and to convey a death signal to B-cell lymphoma 2. B-cell lymphoma 2 is neutralized by BMF and thereby facilitates cytochrome C release from mitochondria. We investigated the role of BMF for intestinal epithelial cell (IEC) homeostasis. Acute colitis was induced in Bmf-deficient mice (Bmf(-/-)) with dextran sulfate sodium. Colonic crypt length in Bmf(-/-) mice was significantly increased as compared with WT mice. Dextran sulfate sodium induced less signs of colitis in Bmf(-/-) mice, as weight loss was reduced compared with the WT. Primary human IEC exhibited increased BMF in the extrusion zone. Quantitative PCR showed a significant up-regulation of BMF expression after initiation of anoikis in primary human IEC. BMF was found on mitochondria during anoikis, as demonstrated by Western blot analysis. RNAi mediated knockdown of BMF reduced the number of apoptotic cells and led to reduced caspase 3 activity. A significant increase in phospho-AKT was determined after RNAi treatment. BMF knockdown supports survival of IEC. BMF is induced in human IEC by the loss of cell attachment and is likely to play an important role in the regulation of IEC survival.

Sphingomyelin induces cathepsin D-mediated apoptosis in intestinal epithelial cells and increases inflammation in DSS colitis.

BACKGROUND: The sphingolipid sphingomyelin is a constituent in food derived from animals. Digestive breakdown of sphingomyelin results in ceramide, recently suggested to be involved in activation of cathepsin D as a novel mediator of apoptosis. Damage of the epithelial barrier was detected in patients with inflammatory bowel disease (IBD) due to increased rates of intestinal epithelial cell (IEC) apoptosis. METHODS: Acute colitis was induced in C57-BL/6 mice with 2.0% dextran sulfate sodium (DSS) over 7 days. Spontaneous colitis was developed in B6-IL10tm1Cgn (interleukin 10-negative (IL-10(-/-))) mice. Mice received 4 or 8 mg sphingomyelin/day by oral gavage. IECs were isolated ex vivo. Apoptosis was determined by propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. Execution of apoptosis was confirmed by analysis of active cathepsin D, caspase-3 and caspase-9 with western blot and immunohistochemistry (IHC). RESULTS: Following DSS-mediated colitis, fluorescence-activated cell sorting (FACS) analysis indicated increased apoptosis of IECs under dietary sphingomyelin. The mean sub-G(1) portion increased from 8.7±2.5% under a normal diet to 14.0±3.1% under dietary sphingomyelin. Cathepsin activity was significantly increased in isolated IECs after gavage of 4 mg of sphingomyelin per day. Western blot and IHC revealed execution of the apoptotic cascade via activated caspase-3 and caspase-9. Dietary sphingomyelin in the IL-10(-/-) model confirmed aggravation of mucosal inflammation. CONCLUSION: Apoptosis of IEC induced by dietary sphingomyelin is mediated via ceramide and cathepsin D activation. This shortens the physiological life cycle of IECs and impairs crucial functions of the intestinal mucosa: barrier, defence and nutrient absorption. The findings provide evidence that dietary sphingomyelin may increase intestinal inflammation.

Management of Immune-Related Adverse Events from Immune-Checkpoint Inhibitors in Advanced or Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICI) are now, among other cancers, routinely used for the treatment of advanced or metastatic renal cell carcinoma (mRCC). In mRCC various combinations of ICIs and inhibitors of the vascular epidermal growth factor receptor tyrosine kinase (VEGFR-TKIs) as well as dual checkpoint inhibition (nivolumab + ipilimumab), the latter for patients with intermediate and poor risk according to IMDC only (international metastatic renal cell carcinoma database consortium), are now standard of care in the first line setting. Therefore, a profound understanding of immune-related adverse events (irAE) and the differential diagnosis of adverse reactions caused by other therapeutic agents in combination therapies is of paramount importance. Here we describe prevention, early diagnosis and clinical management of the most relevant irAE derived from ICI treatment focusing on the new VEGFR-TKI/ICI combinations.

Influence of Prostate Artery Embolization on Different Qualities of Lower Urinary Tract Symptoms Due to Benign Prostatic Obstruction.

BACKGROUND: Prostate artery embolization (PAE) is an increasingly used minimally invasive treatment for lower urinary tract symptoms secondary to benign prostatic obstruction (BPO) OBJECTIVE: To analyze the impact of PAE on voiding and storage symptoms. DESIGN, SETTING, AND PARTICIPANTS: Between July 2014 and May 2019, 351 consecutive men with BPO who underwent PAE were included in a single-center study. INTERVENTION: PAE is an interventional radiological procedure embolizing the prostatic arteries with microspheres. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint represented assessment of the International Prostatic Symptom Score (IPSS) at baseline and at 1, 3, 6, 12, and 24 mo after PAE. Secondary endpoints comprised assessment of IPSS quality of life (QoL), International Index of Erectile Function, peak urinary flow rate, postvoid residual volume, prostate volume, and prostate-specific antigen at the same time points. Data were analyzed using standard statistical methods, generalized estimating equations (symptom improvement over time as odds ratios), and McNemar-Bowker test (degree of improvement compared between symptoms). RESULTS AND LIMITATIONS: Clinical success rates for PAE were 68%, 73%, and 66% at 1, 12, and 24 mo, respectively. The median IPSS improved significantly from 22 to 10 points after 2 yr (p < 0.001). Storage (-50%) and voiding (-58%) symptoms improved similarly (each p < 0.001), with nocturia decreasing least frequently but significantly (p < 0.001). After 1 and 2 yr, 35% (95% confidence interval [CI] 29-41%) and 30% (95% CI 21-40%) of patients reported alleviated storage, and 39% (95% CI 33-45%) and 38% (95% CI 29-49%) reported alleviated voiding symptoms, respectively. QoL improved from 5 to 2 points (p < 0.001). The main limitation is the number of patients lost during follow-up. CONCLUSIONS: PAE significantly improved voiding and storage symptoms to a similar extent. This study may aid in counseling patients about this minimally invasive BPO treatment. PATIENT SUMMARY: Prostate artery embolization (PAE) is a minimally invasive treatment option for patients with voiding and storage symptoms from benign prostate enlargement. Our analysis shows that PAE improves relevant lower urinary tract symptoms.

iRECIST-based versus non-standardized free text reporting of CT scans for monitoring metastatic renal cell carcinoma: a retrospective comparison.

PURPOSE: Therapy decision for patients with metastatic renal cell carcinoma (mRCC) is highly dependent on disease monitoring based on radiological reports. The purpose of the study was to compare non-standardized, common practice free text reporting (FTR) on disease response with reporting based on response evaluation criteria in solid tumors modified for immune-based therapeutics (iRECIST). METHODS: Fifty patients with advanced mRCC were included in the retrospective, single-center study. CT scans had been evaluated and FTR prepared in accordance with center's routine practice. For study purposes, reports were re-evaluated using a dedicated computer program that applied iRECIST. Patients were followed up over a period of 22.8 ± 7.9 months in intervals of 2.7 ± 1.8 months. Weighted kappa statistics was run to assess strength of agreement. Logistic regression was used to identify predictors for different rating. RESULTS: Agreement between FTR and iRECIST-based reporting was moderate (kappa 0.38 [95% CI 0.2-0.6] to 0.70 [95% CI 0.5-0.9]). Tumor response or progression according to FTR were not confirmed with iRECIST in 19 (38%) or 11 (22%) patients, respectively, in at least one follow-up examination. With FTR, new lesions were frequently not recognized if they were already identified in the recent prior follow-up examination (odds ratio for too favorable rating of disease response compared to iRECIST: 5.4 [95% CI 2.9-10.1]. CONCLUSIONS: Moderate agreement between disease response according to FTR or iRECIST in patients with mRCC suggests the need of standardized quantitative radiological assessment in daily clinical practice.

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma.

PURPOSE: Several anti-programmed cell death (ligand)-1 (PD-[L]1) immune checkpoint inhibitors are approved in advanced/metastatic urothelial carcinoma (mUC). Recently, improved activity of an anti-PD-1/anticytotoxic T-cell lymphocyte-4 (CTLA-4) combination versus anti-PD-1 monotherapy has been reported. We report a response-based approach starting treatment with nivolumab monotherapy with nivolumab/ipilimumab as immunotherapeutic boost. METHODS: After four doses of nivolumab induction, responders continued with nivolumab maintenance therapy. Patients with stable/progressive disease received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks for 2 doses followed by nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 2 doses, if not responding to the initial boost. Responders to boosts continued with nivolumab maintenance. Between July 2017 and April 2019, 86 patients were enrolled. The median follow-up is 7.7 months. The primary end point is objective response rate (ORR) per RECIST1.1. Secondary end points include efficacy of nivolumab induction, remission rate with nivolumab/ipilimumab boosts, overall survival, and safety. RESULTS: Of all patients, 42, 39, and five were first- (1L), second- (2L), and third-line (3L), respectively. The median age was 68 years. The ORR with nivolumab monotherapy (assessed at week 8) was 29% in 1L and 23% in 2/3L, respectively. Forty-one patients received early (week 8) and 11 received later nivolumab/ipilimumab boosts. ORRs with nivolumab with or without nivolumab/ipilimumab (best overall response) were 45% and 27% in 1L and 2/3L, respectively. In 1L, 7 of 17 patients receiving boosts at week 8 improved, compared with 2 of 24 in 2/3L. CONCLUSION: The tailored approach of TITAN-TCC shows meaningful clinical activity supporting dual checkpoint inhibition in 1L mUC. However, starting therapy with nivolumab exclusively appears inadequate given the aggressive nature of mUC. In 2/3L, nivolumab/ipilimumab boosts with escalating ipilimumab dose did not improve efficacy outcomes versus nivolumab monotherapy. An independent 2L cohort of TITAN-TCC receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 4 doses is ongoing.

Lack of transketolase-like (TKTL) 1 aggravates murine experimental colitis.

Transketolase-like (TKTL) 1 indirectly replenishes NADPH preventing damage induced by reactive oxygen species (ROS) formed upon intestinal inflammation. We investigated the function of TKTL1 during murine colitis and ROS detoxification for prevention of tissue damage. Mucosal damage in TKTL1(-/-) and wild-type (WT) mice was assessed by miniendoscopy and histology during dextran sodium sulfate (DSS) colitis. mRNA levels of interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF), transketolase (TKT), and TKTL2 were determined by PCR and/or Western blotting. To assess oxidative and nitrosative stress nitrosylation, carbonylation and antioxidative enzymes catalase (Cat), superoxide dismutase 1 and 2, as well as glutathione (GSH) were determined. Myeloperoxidase (MPO) was determined for assessment of tissue neutrophils. TKTL1 knockout or DSS treatment did not influence TKT and TKTL2 mRNA or protein expression. Mucosal damage was significantly increased in TKTL1(-/-) mice indicated by miniendoscopy as well as a significantly shorter colon and more severe histological scores compared with WT mice during DSS colitis. This was associated with higher mRNA levels of IFN-γ, iNOS, IL-6, and TNF. In addition, iNOS protein expression was significantly enhanced in TKTL1(-/-) mice as well as MPO activity. Protein modification by nitric oxide (nitrotyrosine) was induced in TKTL1(-/-) mice. However, introduction of carbonyl groups by ROS was not induced in these mice. The expression of SOD1, SOD2, Cat, as well as GSH content was not significantly changed in TKTL1(-/-) mice. We conclude that induced colitis in TKTL1(-/-) mice was more severe compared with WT. This indicates a role of TKTL1 during mucosal repair and restoration.

Knock-out of ß-glucosidase 2 has no influence on dextran sulfate sodium-induced colitis.

BACKGROUND/AIMS: The non-lysosomal glucosylceramidase, ß-glucosidase (Gba2), hydrolyzes glucosylceramide to glucose and ceramide (Cer). Cer is a potent second-messenger lipid that plays an important role in signaling cascades involved in apoptosis. The aim of this study was to investigate whether Gba2 knock-out (Gba2(-/-)) affects the extent of dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Acute colitis was induced in wild-type (WT) and Gba2(-/-) mice by administration of 2% DSS in drinking water. After 7 days, mice underwent colonoscopy and were sacrificed. RESULTS: Both DSS-treated WT (n = 10) and Gba2(-/-) (n = 12) mice showed elevated histological and endoscopic scores compared to respective H(2)O controls (n = 9 each). However, no significant differences between the DSS groups were detected. Flow cytometric analysis of propidium iodide staining, cleavage of caspases-3 and -8, indicative for apoptosis, as well as Cer levels were not altered in DSS-treated WT or Gba2(-/-) mice. Gba2(-/-) resulted in slightly decreased expression of glucocerebrosidase (Gba1) as well as in upregulation of proteins being involved in cellular regeneration, such as STAT3 (signal transducer and activator of transcription), JNK and iNOS, upon DSS treatment. CONCLUSION: We demonstrate that Gba2(-/-) does not affect the extent of DSS-induced inflammation in mice, however, it might be involved in tissue regeneration in response to toxic agents.

How to Deal with Renal Cell Carcinoma >7 cm: Radical Surgery.

For renal cell carcinoma >7 cm (T2), radical nephrectomy should be the preferred surgical approach because of higher oncologic safety and fewer any-grade and severe complications. The better renal function preservation with partial nephrectomy does not translate into an improvement in overall survival.

Risk Stratification and Treatment Algorithm of Metastatic Renal Cell Carcinoma.

Systemic therapy for metastatic renal cell carcinoma has continuously evolved over the last two decades. Significant improvements in overall survival and quality of life of patients with advanced disease have been observed. With the approval of combination therapies with PD(L)-1 immune checkpoint inhibitors (ICI) as first-line therapy in 2019, the previous standard VEGFR-TKI monotherapy has been replaced as the primary treatment option. In addition to immunotherapy with nivolumab and ipilimumab, three VEGFR-TKI/ICI combinations are now approved. Therapy selection should be preceded by risk stratification using defined criteria from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Clinical parameters, as well as detailed patient counseling on differences in the efficacy profile (response rate, long-term progression-free survival), potential side effects, and impact on quality of life, are of key importance in the individual treatment decision.

[Side effects of immune checkpoint inhibitor treatment of urological tumors]. / Nebenwirkungen der Immun-Checkpoint-Inhibitor-Therapie urologischer Tumoren.

Immune checkpoint inhibitors (ICI) are currently routinely used for the treatment of advanced or metastatic urothelial and renal cell carcinomas. Furthermore, several clinical trials are currently investigating their role in adjuvant and neoadjuvant settings as well as in high-risk non-muscle-invasive bladder cancer. As a result, urologists are increasingly confronted with patients who are currently receiving, have recently received or will receive ICI treatment. Care is often interdisciplinary, with urologists playing a central role. Therefore, a profound understanding of immune-mediated adverse events and their differential diagnoses with respect to side effects of other medications in combination treatment are therefore extremely important. This article focusses on the prevention, early diagnosis and clinical management of the most relevant immune-related side effects derived from the new VEGFR-TKI/ICI combinations.

New First Line Treatment Options of Clear Cell Renal Cell Cancer Patients with PD-1 or PD-L1 Immune-Checkpoint Inhibitor-Based Combination Therapies.

In metastatic renal cell carcinoma (mRCC) the PD-1 immune-checkpoint inhibitor (ICI) Nivolumab became a standard second line treatment option in 2015 based on a significant improvement of overall survival compared to Everolimus. Current pivotal phase 3 studies showed that PD-1 ICI-based combinations were more efficacious than the VEGFR-TKI Sunitinib, a previous standard of care, leading to approval of three new regimens as guideline-recommended first-line treatment. Nivolumab plus Ipilimumab is characterized by a survival advantage, a high rate of complete response and durable remissions in intermediate and poor prognosis patients. Despite frequent immune-mediated side effects, fewer symptoms and a better quality of life were observed compared to Sunitinib. Pembrolizumab or Avelumab plus Axitinib were characterized by an improved progression-free-survival and a high response rate with a low rate of intrinsic resistance. In addition, Pembrolizumab plus Axitinib reached a significant survival benefit. The side effect profile is driven by the chronic toxicity of Axitinib, but there is additional risk of immune-mediated side effects of the PD-1/PD-L1 ICIs. The quality of life data published so far do not suggest any improvement regarding patient-reported outcomes compared to the previous standard Sunitinib. The PD-1/PD-L1 ICIs thus form the backbone of the first-line therapy of mRCC.