Marc-Oliver Grimm

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

BACKGROUND Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. METHODS In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing. FINDINGS Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). INTERPRETATION Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. FUNDING Bristol-Myers Squibb.

Identifying superficial, muscle-invasive, and metastasizing transitional cell carcinoma of the bladder: Use of cDNA array analysis of gene expression profiles

Purpose: Expression profiling by DNA microarray technology permits the identification of genes underlying clinical heterogeneity of bladder cancer and which might contribute to disease progression, thereby improving assessment of treatment and prediction of patient outcome. Experimental Design: Invasive (20) and superficial (22) human bladder tumors from 34 patients with known outcome regarding disease recurrence and progression were analyzed by filter-based cDNA arrays (Atlas Human Cancer 1.2; BD Biosciences Clontech) containing 1185 genes. For 9 genes, array data were confirmed using real-time reverse transcription-PCR. Additionally, Atlas array data were validated using Affymetrix GeneChip oligonucleotide arrays with 22,283 human gene fragments and expressed sequence tags sequences in a subset of three superficial and six invasive bladder tumors. Results: A two-way clustering algorithm using different subsets of gene expression data, including a subset of 41 genes validated by the oligonucleotide array (Affymetrix), classified tumor samples according to clinical outcome as superficial, invasive, or metastasizing. Furthermore, (a) a clonal origin of superficial tumors, (b) highly similar gene expression patterns in different areas of invasive tumors, and (c) an invasive-like pattern was observed in bladder mucosas derived from patients with locally advanced disease. Several gene clusters that characterized invasive or superficial tumors were identified. In superficial bladder tumors, increased mRNA levels of genes encoding transcription factors, molecules involved in protein synthesis and metabolism, and some proteins involved into cell cycle progression and differentiation were observed, whereas transcripts for immune, extracellular matrix, adhesion, peritumoral stroma and muscle tissue components, proliferation, and cell cycle controllers were up-regulated in invasive tumors. Conclusions: Gene expression profiling of human bladder cancers provides insight into the biology of bladder cancer progression and identifies patients with distinct clinical phenotypes.

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

BACKGROUND Nivolumab plus ipilimumab produced objective responses in patients with advanced renal‐cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear‐cell advanced renal‐cell carcinoma. METHODS We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6‐week cycle). The coprimary end points were overall survival (alpha level,0.04), objective response rate (alpha level,0.001), and progression‐free survival (alpha level,0.009) among patients with intermediate or poor prognostic risk. RESULTS A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow‐up of 25.2 months in intermediate‐ and poor‐risk patients, the 18‐month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression‐free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment‐related adverse events occurred in 509 of 547 patients (93%) in the nivolumab‐plus‐ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment‐related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate‐ and poor‐risk patients with previously untreated advanced renal‐cell carcinoma. (Funded by Bristol‐Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749.)

180-W XPS GreenLight Laser Vaporisation Versus Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 6-Month Safety and Efficacy Results of a European Multicentre Randomised Trial—The GOLIATH Study

BACKGROUND The comparative outcome with GreenLight (GL) photoselective vaporisation of the prostate and transurethral resection of the prostate (TURP) in men with lower urinary tract symptoms due to benign prostatic obstruction (BPO) has been questioned. OBJECTIVE The primary objective of the GOLIATH study was to evaluate the noninferiority of 180-W GL XPS (XPS) to TURP for International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) at 6 mo and the proportion of patients who were complication free. DESIGN, SETTING, AND PARTICIPANTS Prospective randomised controlled trial at 29 centres in 9 European countries involving 281 patients with BPO. INTERVENTION 180-W GL XPS system or TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Measurements used were IPSS, Qmax, prostate volume (PV), postvoid residual (PVR) and complications, perioperative parameters, and reintervention rates. Noninferiority was evaluated using one-sided tests at the 2.5% level of significance. The statistical significance of other comparisons was assessed at the (two-sided) 5% level. RESULTS AND LIMITATIONS The study demonstrated the noninferiority of XPS to TURP for IPSS, Qmax, and complication-free proportion. PV and PVR were comparable between groups. Time until stable health status, length of catheterisation, and length of hospital stay were superior with XPS (p<0.001). Early reintervention rate within 30 d was three times higher after TURP (p=0.025); however, the overall postoperative reintervention rates were not significantly different between treatment arms. A limitation was the short follow-up. CONCLUSIONS XPS was shown to be noninferior (comparable) to TURP in terms of IPSS, Qmax, and proportion of patients free of complications. XPS results in a lower rate of early reinterventions but has a similar rate after 6 mo. TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01218672.

Surgery for Metastatic Urothelial Carcinoma with Curative Intent: The German Experience (AUO AB 30/05)

BACKGROUND Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients. OBJECTIVE We report the combined experience and outcome of patients undergoing resection of UCM gained at 15 uro-oncologic centers in Germany. DESIGN, SETTING, AND PARTICIPANTS Retrospective survey of 44 patients with distant UCM of the bladder or upper urinary tract who underwent complete resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008. INTERVENTION Resected metastatic sites were the following: retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). Systemic chemotherapy was administered in 35 of 44 patients (79.5%) before and/or after UCM surgery. MEASUREMENTS Overall, cancer-specific and progression-free survival from time of diagnosis and metastasectomy of UCM. RESULTS AND LIMITATIONS Median survival from initial diagnosis of UCM and subsequent resection was as follows: overall survival, 35 mo and 27 mo; cancer-specific survival, 38 mo and 34 mo; and progression-free survival, 19 mo and 15 mo. Overall 5-yr survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up of 8 mo. Seven patients without disease progression survived for >2 yr and remained free from tumor progression at a median follow-up of 63 mo. No significant prognostic factors could be determined due to the limited patient number. CONCLUSIONS Long-term cancer control and possible cure can be achieved in a subgroup of patients following surgical removal of UCM. Metastasectomy in patients with disseminated UCM remains investigational and should only be offered to those with limited disease as a combined-modality approach with systemic chemotherapy.

A European Multicenter Randomized Noninferiority Trial Comparing 180 W GreenLight XPS Laser Vaporization and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 12-Month Results of the GOLIATH Study

PURPOSE We present the 1-year results of the GOLIATH prospective randomized controlled trial comparing transurethral resection of the prostate to GreenLight XPS for the treatment of men with nonneurogenic lower urinary tract symptoms due to prostate enlargement. The updated results at 1 year show that transurethral resection of the prostate and GreenLight XPS remain equivalent, and confirm the therapeutic durability of both procedures. We also report 1-year followup data from several functional questionnaires (OABq-SF, ICIQ-SF and IIEF-5) and objective assessments. MATERIALS AND METHODS A total of 291 patients were enrolled at 29 sites in 9 European countries. Patients were randomized 1:1 to undergo GreenLight XPS or transurethral resection of the prostate. The trial was designed to evaluate the hypothesis that GreenLight XPS is noninferior to transurethral resection of the prostate on the International Prostate Symptom Score at 6 months. Several objective parameters were assessed, including maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen, in addition to functional questionnaires and adverse events at each followup. RESULTS Of the 291 enrolled patients 281 were randomized and 269 received treatment. Noninferiority of GreenLight XPS was maintained at 12 months. Maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen were not statistically different between the treatment arms at 12 months. The complication-free rate at 1 year was 84.6% after GreenLight XPS vs 80.5% after transurethral resection of the prostate. At 12 months 4 patients treated with GreenLight XPS and 4 who underwent transurethral resection of the prostate had unresolved urinary incontinence. CONCLUSIONS Followup at 1 year demonstrated that photoselective vaporization of the prostate produced efficacy outcomes similar to those of transurethral resection of the prostate. The complication-free rates and overall reintervention rates were comparable between the treatment groups.

Gene signatures of pulmonary metastases of renal cell carcinoma reflect the disease‐free interval and the number of metastases per patient

Our understanding of metastatic spread is limited and molecular mechanisms causing particular characteristics of metastasis are largely unknown. Herein, transcriptome‐wide expression profiles of a unique cohort of 20 laser‐resected pulmonary metastases (Mets) of 18 patients with clear‐cell renal cell carcinoma (RCC) were analyzed to identify expression patterns associated with two important prognostic factors in RCC: the disease‐free interval (DFI) after nephrectomy and the number of Mets per patient. Differentially expressed genes were identified by comparing early (DFI ≤ 9 months) and late (DFI ≥ 5 years) Mets, and Mets derived from patients with few (≤8) and multiple (≥16) Mets. Early and late Mets could be separated by the expression of genes involved in metastasis‐associated processes, such as angiogenesis, cell migration and adhesion (e.g., PECAM1, KDR). Samples from patients with multiple Mets showed an elevated expression of genes associated with cell division and cell cycle (e.g., PBK, BIRC5, PTTG1) which indicates that a high number of Mets might result from an increased growth potential. Minimal sets of genes for the prediction of the DFI and the number of Mets per patient were identified. Microarray results were confirmed by quantitative PCR by including nine further pulmonary Mets of RCC. In summary, we showed that subgroups of Mets are distinguishable based on their expression profiles, which reflect the DFI and the number of Mets of a patient. To what extent the identified molecular factors contribute to the development of these characteristics of metastatic spread needs to be analyzed in further studies.

A Multicenter Randomized Noninferiority Trial Comparing GreenLight-XPS Laser Vaporization of the Prostate and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: Two-yr Outcomes of the GOLIATH Study

BACKGROUND The GOLIATH study is a 2-yr trial comparing transurethral resection of prostate (TURP) to photoselective vaporization with the GreenLight XPS Laser System (GL-XPS) for the treatment of benign prostatic obstruction (BPO). Noninferiority of GL-XPS to TURP was demonstrated based on a 6-mo follow-up from the study. OBJECTIVE To determine whether treatment effects observed at 6 mo between GL-XPS and TURP was maintained at the 2-yr follow-up. DESIGN, SETTING, AND PARTICIPANTS Prospective randomized controlled trial at 29 centers in nine European countries involving 281 patients with BPO. INTERVENTION Photoselective vaporization using the 180-W GreenLight GL-XPS or conventional (monopolar or bipolar) TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the International Prostate Symptom Score for which a margin of three was used to evaluate the noninferiority of GL-XPS. Secondary outcomes included Qmax, prostate volume, prostate specific antigen, Overactive Bladder Questionnaire Short Form, International Consultation on Incontinence Questionnaire Short Form, occurrence of surgical retreatment, and freedom from complications. RESULTS AND LIMITATIONS One hundred and thirty-six patients were treated using GL-XPS and 133 using TURP. Noninferiority of GL-XPS on International Prostate Symptom Score, Qmax, and freedom from complications was demonstrated at 6-mo and was sustained at 2-yr. The proportion of patients complication-free through 24-mo was 83.6% GL-XPS versus 78.9% TURP. Reductions in prostate volume and prostate specific antigen were similar in both arms and sustained over the course of the trial. Compared with the 1(st) yr of the study, very few adverse events or retreatments were reported in either arm. Treatment differences in the Overactive Bladder Questionnaire Short Form observed at 12-mo were not statistically significant at 24-mo. A limitation was that patients and treating physicians were not blinded to the therapy. CONCLUSIONS Twenty-four-mo follow-up data demonstrated that GL-XPS provides a durable surgical option for the treatment of BPO that exhibits efficacy and safety outcomes similar to TURP. PATIENT SUMMARY The long-term effectiveness and safety of GLP-XLS was similar to conventional TURP for the treatment of prostate enlargement.

Assessment of PI-RADS v2 for the Detection of Prostate Cancer

PURPOSE To evaluate the diagnostic performance and inter-reader reliability of the multiparametric magnetic resonance imaging (mpMRI) based prostate imaging reporting and data system (PI-RADS) version 1 and version 2 for the assessment of prostate cancer. MATERIAL AND METHODS A cohort of 82 patients underwent endorectal mpMRI at 1.5T. Patients had at least one lesion with a PI-RADS v1 assessment category of ≥3 and were selected for targeted in-bore MR-guided biopsy in a subsequent session. The results of the histopathological workup were used as reference standard. All lesions were retrospectively evaluated according to PI-RADS v2 by an experienced and unexperienced blinded reader. Diagnostic performance was compared by analyzing the area under the Receiver Operating Characteristics Curve (AUC). The weighted kappa method was used to calculate inter-reader reliability. RESULTS Targeted MR-guided biopsy was performed in 136 lesions and revealed 39 malignant lesions in 31 patients. AUC values increased for the experienced reader (PI-RADS v1 0.79; PI-RADS v2 0.83) and unexperienced reader (PI-RADS v1 0.70; PI-RADS v2 0.83). When excluding the cases of low grade cancer (Gleason score=3+3), AUC values increased further for the experienced reader (PI-RADS v1 0.88; PI-RADS v2 0.91) and unexperienced reader (PI-RADS v1 0.78; PI-RADS v2 0.90). Specificity at the selected threshold of a PI-RADS v1/v2 assessment category ≥4 improved for both readers. Inter-reader agreement increased from κ=0.55 in PI-RADS v1 to κ=0.68 in v2. CONCLUSION PI-RADS v2 improved diagnostic performance for the assessment of suspicious intraprostatic lesions identified in PI-RADS v1 for both readers and led to higher inter-reader reliability. These results suggest that PI-RADS v2 is a reliable and replicable reporting system for the assessment of prostate cancer.

DNA methylation alterations in urothelial carcinoma.

In urothelial cancer, hypermethylation of specific genes and genome-wide hypomethylation, reflected in decreased methylation of LINE-1 retrotransposons, have both been reported, but were never investigated in the same specimens. We analyzed hypermethylation of 6 genes by methylation-specific PCR and LINE-1 hypomethylation by Southern blotting in 96 carcinoma tissues. Hypermethylation frequencies were: SFRP1 (55%), APC (45%), RASSF1A (35%), DAPK1 (29%), RARB2 (19%), and CDKN2A (2%). Three groups of cancers could be discerned, with escalating hypermethylation. Hypermethylation increased with tumor stage, particularly at the transition to invasive cancers, and RARB2 hypermethylation was indicative of lymph node involvement. A comparison to a previous study on prostate cancer using the same techniques suggests that hypermethylation in urothelial carcinoma occurs in a random rather than coordinated manner. LINE-1 hypomethylation was present in 90% of specimens, largely independent of hypermethylation. Lack of hypomethylation indicated a significantly better clinical prognosis. Bisulfite sequencing of SFRP1 demonstrated dense or patchy hypermethylation in tumor tissues that likely accounts for discrepant reported frequencies. In urothelial carcinoma cell lines, the same genes as in tissues were frequently hypermethylated. SFRP1 hypermethylation was concordant with lack of expression. 5-Aza-deoxycytidine induced its reexpression in some lines, whereas additional treatment with a histone deacetylase inhibitor was required in others. Thus, epigenetic SFRP1 inactivation occurs in a graduated manner. In conclusion, markers of genome-wide hypomethylation seem optimally suited for urothelial carcinoma detection, whereas combinations of hypermethylation and hypomethylation assays hold promise for classification.