bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes of hypoxia modification in bladder preservation: Update from BCON trial.
Authors: Song Yee Pei , Mistry Hitesh , Choudhury Ananya , Hoskin Peter
Published: March 2019

356

Background: The mainstay of radical organ preserving treatment in muscle-invasive bladder cancer is radiotherapy (RT). Radiosensitising agents have been shown to improve treatment response and survival. Chemoradiotherapy is the most commonly used regime, however, hypoxia modification has also been shown to be effective. BCON is a phase III clinical trial which showed that the addition of carbogen and nicotinamide (CON) significantly improved recurrence-free survival (RFS) and overall survival (OS) (Hoskin et al, 2010). The long term outcomes twelve years after the trial closed to recruitment are reported. Methods: Outcomes from the original BCON trial were updated and analysed. Patients excluded from the original analysis were excluded once again. Cox regression analysis adjusted for known prognostic factors was performed. Results: 333 patients were randomized to receive RT alone or RT+CON. 9 patients from the RT+CON arm and 3 from RT alone arm were excluded from the analysis. The median age of patients in both arms was 74 (51-90) and the median follow-up was 10.3 years. There was a statistically significant improvement in 5 year RFS (41% vs 33%, p = 0.04) with the difference maintained at 10 years (27% vs 20%). The 5 year OS was 49% vs 40% (p = 0.068) with a continued effect seen at 10 years when OS was 32% vs 24%. These differences remained following adjustment for known prognostic factors. Conclusions: The survival advantage for CON in the original analysis which demonstrated a significantly improved 3 years OS (59% vs 47%, p = 0.020) is maintained in long term follow up. At 5 years there is a statistically significant improvement in RFS and at 5 and 10 years the addition of hypoxia modification to radiotherapy continues to show an impact on overall survival, These results confirm a sustained benefit of hypoxia modification in bladder preservation treatment for muscle-invasive bladder cancer. Clinical trial information: NCT00033436.
Molecular profiling of aggressive variant urothelial carcinoma.
Authors: Ramamurthy Chethan , Arguello David , Anari Fern , Ghatalia Pooja , Zibelman Matthew R. , Plimack Elizabeth R. , Burgess Earle Frederick , Hogan Thomas F. , Dawson Nancy Ann , Hauke Ralph J. , Aragon-Ching Jeanny B. , Vaena Daniel A. , Heath Elisabeth I. , Geynisman Daniel M.
Published: March 2019

378

Background: The WHO recognizes multiple variant histologies of urothelial carcinoma (vUC), many of which have been associated with poor outcomes compared with urothelial carcinoma (UC). We aimed to explore molecular differences between aggressive vUC and UC. Methods: 23 micropapillary (MP), 16 plasmacytoid (P), 23 sarcomatoid (S), 7 nested (N), 6 clear cell (CC), and 2 giant cell (GC) vUC specimens were tested between 2012 to 2018 via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or NGS), and protein expression (immunohistochemistry [IHC]). Findings were compared to 435 control UC specimens using the Chi-square test. Results: 84% of samples were from primary tumor. Alterations identified are summarized in Table 1, and are notable for high rates of TP53 mutations across histologic subtypes, varying rates of RB1, ERBB2 and FGFR mutations, and overall low rates of DNA damage repair (DDR) mutations (29 genes reported) except in S. There were more ARID1A mutations detected in MP than UC (100% [3 specimens] v. 41.3%, p=0.044), and more CDH1 mutations in P than UC (50% [4 specimens] v. 2%, p<0.001). CISH ERBB2 (HER2) amplification was seen in 27.3% MP compared with only 10.4% in UC (p=0.005). Compared to UC, PD-L1 IHC (SP142 assay) was positive (>5%) in a high proportion of S (55.6%, p=0.002) but in a lower proportion of other vUC (e.g. absent in P). Tumor mutational burden (TMB) was high in a lower proportion of vUC: 18.4% UC vs. 14.3% MP, 0% P, 16.7% S. Conclusions: Aggressive variant histology UCs have a differential profile of molecular aberrations compared to UC, with notable differences in potential targets such as HER2 and DDR genes as well as immunotherapy biomarkers. Further studies are needed to confirm these findings, and may support therapy development for these rare, aggressive UC subtypes. Aberrations (%) in Variant Histology UC. [Table: see text]
Do elderly men (>75) harbor more aggressive prostate cancer? Comparison of decipher and PAM50 TESTS among different age groups.
Authors: Goldberg Hanan , Herrera Cáceres Jaime Omar , Santiago-Jimenez Maria , Fishbane Nicholas , Davicioni Elai , Klaassen Zachary William Abraham , Chandrasekar Thenappan , Wallis Christopher , Woon Teck Sing , Hamilton Robert James , Kulkarni Girish S. , Berlin Alejandro , Fleshner Neil Eric
Published: March 2019

38

Background: Age is an important prognostic factor in oncology. Over 20% of men diagnosed with prostate cancer (PC) are ≥ 75 years old. In the growing elderly population, objective methods for predicting outcomes beyond chronologic age are necessary in order minimize the likelihood of withholding curative treatment when warranted. Herein, we describe and analyze age-related differences in clinico-genomic prognostic indices of aggressiveness in localized PC. Methods: Clinical and genomic data for 8,355 patients from the Decipher Genomic Resource Information Database was obtained. Conventional and genomic prognostic indices including Decipher GC scores, PAM50 molecular subtypes (e.g. luminal A/B or basal) NCCN risk groups and Gleason groups (GG) were stratified by age using multivariable logistic regression analyses (MLRA). Results: With increasing decile of age, we observed a higher proportion of high GG and higher Decipher scores. There was a statistically significant increase in the proportion of patients with high Decipher scores with increasing age among GG1 and GG2 (< 55-10.2%, 30.7%, 55-60-15.4%, 25.6%, 60-65-15.9%, 29.7%, 65-70-16.9%, 28.2%, 70-75-17.9%, 30%, and > 75-20.3%, 37.3%, respectively). Furthermore, the prevalence of the PAM50 luminal B subtype (associated with worse prognosis) increased with age among GG1 and GG2 (< 60-22.2%, 40%, 60-65-29.1%, 41.7%, 65-70-28.2%, 39.2%, 70-75-30%, 43.4%, 75-80-33.5%, 44.3%, > 80-34.2%, 52%, respectively). Among higher grade tumors (GG 3-5), no statistically significant differences between the different age groups were observed. MLRA demonstrated that in addition to higher T stage, PSA and GG, each age decile entailed a 20% increased risk for a high Decipher score (OR 1.2, 95% C.I 1.11-1.3, p < 0.001). Conclusions: Older men with lower grade tumors, as opposed to higher grade tumors, harbored worse disease based on genomic risk models. The accepted paradigm of elderly PC patients being treated conservatively based solely on chronologic age, needs to be changed. We provide evidence suggesting the utility of clinical-genomic characterization for better treatment individualization decisions. (GRID; NCT02609269).
Treatment (tx) characteristics of patients (pts) with locally advanced or metastatic urothelial cancer (mUC) receiving atezolizumab (atezo) monotherapy in United States clinical practice.
Authors: Mhatre Shivani K. , Chuo Ching-Yi , Morgans Alicia K. , Rahma Osama E. , Pachynski Russell Kent , Martinalbo Jorge , Davarpanah Nicole N. , Davies Jessica
Published: March 2019

381

Background: Atezo (anti–PD-L1) was the first immune checkpoint inhibitor approved for mUC. Here, we describe pt characteristics, time on tx (TOT) and distribution of tx cycles for pts receiving atezo in clinical practice, to complement data from clinical trial setting. Methods: Pts diagnosed with mUC who initiated atezo monotherapy in the first-line (1L) or second-line and beyond (2L+; prior platinum tx) settings on or before Jun 30, 2017, were identified from the US-based Flatiron Health electronic health record–derived database. Tx data were analyzed through Mar 31, 2018. TOT was defined as time from first to last atezo administration, plus 1 cycle length. Median TOT was calculated by tx line using the Kaplan-Meier method. Tx cycles were calculated by the number of atezo doses received during TOT. Corresponding results from global atezo clinical trials are presented. Results: Real-world data (RWD) from 312 pts (n = 102, 1L; n = 210, 2L+) met the study selection criteria (Table). Median TOT was 3 and 3.5 months in the 1L and 2L+ settings, respectively, with 95% CIs overlapping with the trial TOT data. A median of 4 cycles (IQR, 2-7, 1L; 2-9, 2L+) was administered in both settings. Conclusions: This is the first study of RW atezo use in mUC. The TOT with atezo observed in a US RW setting and the clinical setting (IMvigor210/IMvigor211) was similar. [Table: see text]
Radiotherapy-induced immunogenic effects in bladder cancer.
Authors: Walshaw Richard , Honeychurch Jamie , Roberts Joanne , Swan Jacqueline , Dean Laura , Choudhury Ananya , Illidge Tim
Published: March 2019

418

Background: Many patients with bladder cancer (BC) undergo radiotherapy (RT) during the course of their treatment. There is emerging evidence that RT can cause immune stimulatory changes within the tumour microenvironment (TME), potentially contributing to its efficacy. We aimed to determine if RT induces immunogenic changes in murine BC cell lines, and develop a pre-clinical model of BC with a TME reflective of de novo tumours in order to test this premise in vivo. Methods: Immunogenic effects of RT were determined using murine vaccination studies with irradiated tumour cells. RT-induced immuno-phenotypic changes in surface antigen expression on tumour cells were ascertained using flow cytometry. An orthotopic BC model was established using MBT2 cells instilled intravesically in C3H/Hen mice, and resulting tumours monitored with ultrasound (US). We used immunohistochemical (IHC) staining to determine the immune contexture of the TME within developing orthotopic tumours. Results: C57BL/6 mice inoculated with irradiated MB49 cells demonstrated improved survival compared to control mice after subsequent rechallenge with viable tumour cells. This effect was not seen in C3H mice implanted with irradiated MBT2 cells. RT led to upregulation of immune stimulatory molecules CD80, MHC I, and Fas on MB49 but not MBT2 cells. Tumours developed in 80% of mice following catheter implant, and visible on US 3-4 weeks after instillation. Profiling of the TME with IHC demonstrated that tumours contained few CD8+ T-cells, but high numbers of myeloid cells. Conclusions: RT induces immune stimulatory effects on murine BC cells, including upregulation of several surface proteins. In future work, we will determine the effects of RT on the TME in the orthotopic model, and correlate these with the expression of various immunogenic cell surface proteins. This may lead to the discovery of a biomarker to predict which patients with BC would benefit from combination of an immunomodulatory agent with RT.
Predictive value of fibroblast growth factor receptor (FGFR) mutations and gene fusions on anti-PD-(L)1 treatment outcomes in patients (pts) with advanced urothelial cancer (UC).
Authors: Santiago-Walker Ademi E. , Chen Fei , Loriot Yohann , Siefker-Radtke Arlene O. , Sun Libo , Sundaram Ramesh , De Porre Peter , Patel Kiran , Wan Ying
Published: March 2019

419

Background: FGFR alterations have been shown to be associated with immunologically “cold” UC tumors with low immune marker expression and T cell infiltrate, a poorly receptive environment for immune checkpoint inhibitors. Using a real world matched clinical and genomic dataset of pts with advanced UC, we explored their predictive value in pts receiving anti-PD-(L)1 therapy. Methods: The Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) contained full clinical and treatment information and molecular data on a cohort of pts with confirmed advanced UC. The populations of interest are FGFR+ and FGFR- patients determined by the presence or absence of a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS), measured from the start of anti-PD-(L)1 therapy, was analyzed using Kaplan-Meier estimation and Cox proportional hazards models adjusted for left truncation (delayed entry model). Results: 118 pts ( FGFR+ n = 26, FGFR- n = 92) treated with anti-PD-(L)1 therapy for advanced UC were assessed for OS. Median OS for FGFR+ pts who received any line of anti-PD-(L)1 therapy (n = 26) was 3.1 mo vs 6.1 mo for FGFR- pts (n = 92) (hazard ratio [HR] 1.33, 95% CI 0.78-2.26, p = 0.30). For first-line anti-PD-(L)1 therapy, median OS in FGFR+ pts (n = 12) was 4.7 mo vs 11.3 mo for FGFR- pts (n = 28) (HR 1.94, 95% CI: 0.78-4.82, p = 0.15); median OS in second-line were 3.1 mo (n = 12) vs 6.1 mo (n = 47), respectively (HR 1.17, 95% CI 0.53-2.59, p = 0.70). Per multivariate analysis, FGFR+ status appears to be associated with poorer OS in pts treated with any line of anti-PD-(L)1 therapy (HR 1.25, 95% CI 0.71-2.21, p = 0.43). Conclusions: These real-world data suggest that FGFR+ pts following anti-PD-(L)1 therapy for advanced UC may be associated with a trend in poorer overall survival outcome compared with FGFR- pts. These findings are in alignment with treatment history data from BLC2001 (Siefker-Radtke A, et al. ASCO-GU 2018), which showed low response rates to prior anti-PD-(L)1 therapies among FGFR+ pts.
Analysis of FGFR alterations from circulating tumor DNA (ctDNA) and Tissue in a phase II trial of erdafitinib in urothelial carcinoma (UC).
Authors: Santiago-Walker Ademi E. , Moy Christopher , Cherkas Yauheniya , Loriot Yohann , Siefker-Radtke Arlene O. , Motley Clifford , Avadhani Anjali Narayan , OHagan Anne , De Porre Peter , Lorenzi Matthew V. , McCaffery Ian
Published: March 2019

420

Background: Plasma samples from a Phase 2 study of the pan-FGFR inhibitor erdafitinib in advanced UC patients (pts) with FGFR mutations (mut) or fusions, were tested using next generation sequencing (NGS) for circulating tumor DNA (ctDNA), and results compared to central FGFR status determination from tissue. Methods: FGFR alterations were measured in archival tissue using an RNA-based RT-PCR test and compared with FGFR alterations identified in pre-treatment plasma specimens using the Guardant360 ctDNA test. Sensitivity of the ctDNA test to detect the FGFR alterations identified by RT-PCR from tissue, the proportion of pts with a study-eligible FGFR alteration in ctDNA, and the ability to detect a tissue FGFR alteration in ctDNA in relation to clinical response were assessed. Results: Samples from 155 pts with detectable baseline ctDNA were included. Overall, concordance between ctDNA and tissue-based FGFR results was 56% (87/155): 63% (77/122) for tissue mut-positive pts vs 24% (7/29) in fusion-positive pts. 61% of pts (94/155) were positive for a study-eligible FGFR alteration from blood-based testing in the tissue-positive population. The response rate was 47% (36/77) for patients for which FGFR mutations could be detected in blood (ctDNA- FGFR-positive) compared with 32% (14/44) in patients for which mutations were not detected in blood (ctDNA- FGFR-negative), with an estimated odds ratio of 1.882 (95% CI: 0.866; 4.090) Conclusions: The 63% concordance rate for detecting FGFR mut in temporally unmatched blood and tissue supports potential for patient selection with blood-based testing, while ctDNA FGFR fusion detection may require further optimization. Although differences in clinical response rate were observed between ctDNA- FGFR-positive and negative patients, the results were not statistically significant. Importantly, a proportion of ctDNA-negative pts responded to erdafitinib, indicating that tissue-based testing may be warranted for pts negative for FGFR alterations via blood-based testing. (BLC2001, NCT02365597). Clinical trial information: NCT02365597.
Association of the commensal urinary microbiome with response to Bacillus Calmette-Guérin (BCG) immunotherapy in nonmuscle invasive bladder cancer.
Authors: Sweis Randy F. , Golan Shay , Barashi Nimrod , Hill Elle , Andolfi Ciro , Werntz Ryan P. , Bloodworth Jeffrey , Steinberg Gary D.
Published: March 2019

423

Background: Standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical BCG. Despite its established efficacy, up to 50% of patients may recur. The development of predictive biomarkers for BCG immunotherapy would enhance treatment algorithms and potentially uncover mechanisms of resistance. Recent data have characterized the presence of a commensal urine microbiome, but its role in BCG-treated NMIBC patients remains unexplored. We assessed the composition of the urine microbiome in NMIBC patients and evaluated associations with response to therapy. Methods: Patients with a newly diagnosed bladder tumor were enrolled prior to TURBT on an institutional review board-approved study at a single institution. Adjuvant BCG instillation was administrated to high-risk patients according to the surgical histology. Urine samples for microbiome assessment were collected by catheterization to eliminate urethral contamination before the TURBT and up to 8 additional timepoints. 16S sequencing and analysis was performed on baseline specimens prior to BCG. Results: Among 31 patients enrolled, 10 (32%) recurred and 21 (68%) had no recurrence with a median follow up of 6 months. Median age was 69 years (range 46-87), and 9 (29%) patients were female and 22 patients (71%) were male. The most abundant phyla observed were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. Together these accounted for > 99% of the phyla detected in the cohort. Global analysis of distances by operational taxonomic units (OTUs) indicated a significant difference between patients with and without recurrence (Bonferroni-corrected P = 0.017). The abundance of Proteobacteria was higher in patients with recurrence (P = 0.035), with stronger differences observed for specific classes such as Gammaproteobacteria (P = 0.0025). Firmicutes such as Lactobacillales were more abundant in patients without recurrence (P = 0.049). Conclusions: In this study we detected variation in the composition of the urine microbiome in NMIBC patients, which may predict response to BCG immunotherapy. Further studies to confirm these results are ongoing.
Impact of bone metastasis on clinical outcomes in metastatic urothelial bladder cancer (mUC) for patients treated with first-line platinum-based chemotherapy.
Authors: Riromar Jamila Jama Almi , Veitch Zachary William Neil , Sacher Adrian G. , Maganti Manjula , Fallah-Rad Nazanin , Hansen Aaron Richard , Sridhar Srikala S.
Published: March 2019

431

Background: Prognostic nomograms have identified patients with mUC less likely to benefit from treatment. Yet, analyses have relied on grouped patient variables (ie: bone plus visceral metastases) and refinement is needed. This study aims to evaluate the clinical outcomes of bone metastases (BM) on patients with mUC treated with first-line platinum-based chemotherapy. Methods: Patients receiving first-line platinum-based chemotherapy for mUC at the Princess Margret Cancer Centre from 12/2009-10/2016 were selected from central pharmacy records. Patient and tumor characteristics, in addition to treatment history were collected retrospectively. Oncologist assessed best response (OABR; complete [CR] or partial [PR] response; stable (SD] or progressive [PD] disease) was evaluated by chart review. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier (log-rank). Overall response rate (ORR) was calculated from OABR. Multivariable analysis (MVA) was performed using Cox-regression. Significance was evaluated at the p < 0.05 level. Results: Of 112 patients receiving platinum-based chemotherapy, 62 (55%) had mUC. Most patients were male (73%), had ECOG PS of 0-1 (71%), and de novo metastases (23%). Patients received a median of 5 chemotherapy cycles (range 1-8), and median follow-up was 12.7 months. Number of organs involved with metastases varied (1 = 32%; 2 = 45%; 3+ = 23%); with lymphnode (77%), bone (37%), and lung metastases (34%) frequently involved. Median PFS (months) was shorter (p < 0.05) in patients with BM (5.6; 95%CI:2.7-7.0) compared to no BM (8.0; 95%CI:6.5-9.5). Median OS (months) was shorter (p < 0.05) in patients with BM (8.9; 95%CI:7.2-15.9) compared to no BM (16.1; 95%CI:10.5-23.4). ORR was lower for those with BM (22%) compared to no BM (56%). MVA using BM and prognostic nomogram criteria showed significance for ECOG 2+ (HR = 2.72; p < 0.05) with a trend towards significance for BM (HR = 1.85; p = 0.06). Conclusions: mUC patients with BM have lower response and inferior survival by log-rank. This could have direct implications for clinical decision making and stratification of factors in clinical trials.
Tumor mutational burden (TMB) and BCG responsiveness in high-risk non-muscle invasive bladder cancer (NMIBC).
Authors: Bastos Diogo Assed , Lima Mariana , Mattedi Romulo Loss , dos Santos Filipe Ferreira , Buzatto Vanessa , Barreiro Rodrigo , Ribeiro-Filho Leopoldo , Cordeiro Mauricio , Amano Mariane , Souza Jussara Michaloski , Bettoni Fabiana , Galante Pedro Alexandre Favoretto , Dzik Carlos , Nahas William Carlos , Camargo Anamaria Aranha
Published: March 2019

442

Background: Despite optimal management of NMIBC with transurethral resection of bladder tumor (TURBT) and intravesical BCG therapy, a significant proportion of patients (pts) will eventually present with disease recurrence or progression. To date, there is no validated predictive biomarker to guide patient selection for the most appropriate therapy in this setting. Methods: We retrospectively identified pts with high-risk NMIBC treated with TURBT, repeat TUR and intravesical BCG (≥ 6 instillations) from 2009 to 2016. Patients were classified as BCG-responsive (BCG-R) and BCG-unresponsive (BCG-UR) based on the International Bladder Cancer Group criteria. Whole exome sequencing was performed using archival FFPE tumor tissue from pre-BCG TURBT samples. Association of genomic variables and outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. Results: Thirty-five patients were included (BCG-R = 17, BCG-UR = 18). Median follow-up was 46 months for BCG-R and 52 months for BCG-UR pts. The majority of pts was male (91.4%), former smoker (60%), and presented with high-grade urothelial carcinoma (85.7%) and/or T1 staging (71.4%). Median time for relapse and progression was 10.5 and 19 months, respectively, in the BCG-UR group. In this cohort, TMB was significantly different in BCG-R and BCG-UR groups, with a median TMB of 5.53 +- 4.60 and 3.17 +- 1.82 mutations/Mb, respectively ( P= 0.045). TMB was also associated with relapse-free survival (RFS), with a median RFS of 38 and 15 months in high versus low TMB groups, respectively ( P= 0.0092). Intratumoral genetic heterogeneity assessed by mutant-allele tumor heterogeneity (MATH) was not statistically different between the groups, with a median MATH score of 31.8 and 21.9 for BCG-R and BCG-UR ( P= 0.14), respectively. On multivariate analysis, age and TMB were independently associated with RFS. Conclusions: In this exploratory biomarker study, high TMB was associated with benefit from immunotherapy with BCG for NMIBC. The identification of predictive biomarkers in this setting is an important unmet need and integrative analysis of TMB with other potential predictive biomarkers should be assessed in larger datasets.
Evaluation of prognostic effects of MSI, PD-L1 and TIL in resected bladder cancer.
Authors: Tural Deniz , Akar Emre , Baytekin Halil Firat , Tugcuoglu Volkan
Published: March 2019

465

Background: The aim of the study was evaluating prognostic significance of tumor infiltrating lymphocytes (TIL), microsatellite instability (MSI) and programmed cell death ligand-1 (PD-L1) expression which are used as predictive biomarkers in immunotherapy. Methods: Clinic and pathologic features of bladder cancer patients who were underwent radical cystectomy were retrospectively analyzed from patients’ records in this single-center study. PD-L1, PD-L1 in TIL, PMS2, MSH2, MSH6 and MLH1 immunohistochemistry staining were carried out to archived resected tumor specimens of the eligible patients. MSI was evaluated according to existing of PMS2, MSH2, MSH6 and MLH1. Results: Fifty-six males (91.8%) and 5 females (8.2%) of total 61 patients were eligible for the study. Median age was 61.72 (35-81). PD-L1 expression in tumor cells and PD-L1 expression in TIL were positive in 14,8% (n = 9) and 16.4% (n = 10) of total 74 patients, respectively. MSI was high in 15 patients (24.6%). Intratumoral TIL rate was < 10% in 49 patients (80.3%) while > 10% in 12 patients. (19.7%) In Chi-square test, there was no statistically significant relationship between PD-L1, PD-L1 in TIL, MSI and TIL rate and patients’ characteristics including sex, stage, pathologic grade and lymph node status. Three-years overall survival (OS) rate was calculated as 43%. Univariate analysis did not reveal any significant difference in 3-years OS in PD-L1 expression in tumor, PD-L1 expression in TIL and TIL rate > 10% . (p = 0.822, p = 0.638, p = 0.318; respectively ). There was a positive trend with MSI high patients and OS (p = 0.089). At also; age and stage showed statistically significant difference in multivariate analysis. (p = 0.023, p = 0.011, respectively). Conclusions: This study revealed that there is no prognostic significance of PD-L1 and TIL. However, there are positive trend between OS and MSI, which is proven as predictive biomarker of immunotherapy, in patients who were followed with same treatment and follow-up approach in single center. These results must be corroborated with large and prospective investigations in order to better understanding biology and behavior of bladder cancer.
Durable clinical benefit from combination ipilimumab (IPI) and nivolumab (NIVO) in anti-PD-1 therapy resistant, platinum resistant metastatic urothelial carcinoma (mUC).
Authors: Keegan Niamh M. , Funt Samuel Aaron , Kania Brooke Elizabeth , Iyer Gopa , Clement Jessica Mary , McCoy Asia S. , Hettich Grace , Ziv Etay , Maher Colleen Anne , Nair Suresh , Panageas Katherine , Bluth Mark J. , Wong Phillip , Wolchok Jedd D. , Rosenberg Jonathan E. , Bajorin Dean F. , Callahan Margaret K.
Published: March 2019

481

Background: Overcoming resistance to anti-PD-1 therapy in UC patients (pts) is of major interest given the modest single agent response rates for pts with mUC. Herein we report the outcome of combined NIVO and IPI in pts who progressed on single agent NIVO. Methods: This prospective, open label, adaptive study treated platinum resistant mUC pts with NIVO monotherapy with the designated intent to add IPI at disease progression. RECIST 1.1 assessments were performed every 6 wks for 24 wks then every 12 wks. Primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS) and possible associations between clinical endpoints and tumor genomic characteristics. Next generation sequencing (NGS) was performed to assess DNA Damage Response (DDR) gene mutations and Tumor Mutation Burden (TMB). Results: To date, 21 pts who progressed after NIVO monotherapy have received IPI plus NIVO. ORRs to prior NIVO monotherapy were variable; partial response (PR = 4/21, 19%), stable disease (SD = 6/21, 29%) and progressive disease (PD = 11/21,52%). 57% (12/21) had visceral metastases. For IPI + NIVO the ORR was 19% (PR: n=4, CR: n=0) and duration of response >12 mo in a subset; 2 pts with PR remain on treatment (3+, 5+ mo), 1 pt has an ongoing PR (13+ months) after stopping treatment due to toxicity. Responding disease sites include node, liver and lung. Immune-related toxicity ≥ G3 seen in 9 pts (43%), of whom 4 (44%) had disease control (PR+SD≥3mo). No correlation detected between clinical outcome and TMB or DDR mutations. Conclusions: IPI plus NIVO responses can be seen in pts with NIVO resistance and the benefit from combined checkpoint blockade can be prolonged. Immune related toxicity frequently accompanied disease control. TMB and DDR were not associated with benefit in this small cohort; immune correlative analyses are ongoing. Clinical trial information: NCT02553642. [Table: see text]
The PRIMETEST trial: Interim analysis of a phase II trial for primary retroperitoneal lymph node dissection (RPLND) in stage II A/B seminoma patients without adjuvant treatment.
Authors: Albers Peter , Hiester Andreas , Grosse Siemer Robert , Lusch Achim
Published: March 2019

507

Background: We thought to evaluate progression-free survival of stage II A/B seminoma patients (pts) undergoing primary retroperitoneal lymph node dissection (RPLND) without adjuvant treatment. Aim is to present interim data of a feasibility study and a phase II trial. Methods: Prior to the phase II study, 9 patients have been treated within a pilot feasibility study. After IRB approval, additional 12 patients from 3/2016 to 9/2018 within the prospective phase II trial were accrued. All patients received primary retroperitoneal lymph node dissection (open or daVinci assisted) for stage IIA/B seminoma without adjuvant treatment. The data was analyzed for peri- and postoperative outcome including recurrence free survival. The trial will have to accrue 30 pts and was designed to exclude a > 30% recurrence to standard treatment. Results: Since 5.2014 twenty-two patients with seminomateous germ cell tumor have been included in both studies, including one patient with an atypical inguinal recurrence and one patient with a 6 cm marker negative recurrence (clinical stage IIC). Primary RPLND was performed in 4 patients with initial CSIIA. 14 and 4 patients experiences a recurrence under surveillance and after carboplatin adjuvant treatment, respectively. Mean tumor size was 2.6 cm with a mean OR time of 134 min and a mean blood loss of 70 cc. One patient after DaVinci RPLND developed a ureteral stricture requiring ileal ureter substitute. The mean follow-up is 24 month (range 1-51 months), 17/22 patients (77%) are free of recurrence. 5/22 (23%) developed a recurrence (4x outside field and 1x inside field) with a mean time to recurrence of 4.5 months. All patients received salvage treatment (4x CTX and 1x radiotherapy) and are currently recurrence free. Conclusions: Primary RPLND in stage IIA/B seminoma patients is an experimental treatment approach in order to reduce long term toxicity and secondary malignancies. Interim results of this strategy justifies continuation of the study. This kind of surgery should only be performed within clinical trials in high volume referral centers. Clinical trial information: NCT 2015053664.
Increasing adipose burden in young men with metastatic testicular cancer following front-line cytotoxic chemotherapy.
Authors: Arora Karan Kumar , Kato Caroline , Batra Kunnal , Mullane Michael Russell , Lad Thomas E. , Master Viraj A. , Psutka Sarah P.
Published: March 2019

525

Background: Exposure to cytotoxic chemotherapy (CC) has been observed to be associated with significant changes in body composition, namely marked lean muscle mass losses, with implications for treatment-related toxicity and oncologic outcomes. However, prior studies predominately include elderly patients who, a priori, are at risk for sarcopenia or severe skeletal muscle deficiency. To date, the impact of CC on body composition in young men with testicular cancer remains undefined. Methods: A retrospective analysis of 19 patients with metastatic testicular cancer treated with CC was performed (2015-17). Lumbar skeletal muscle index (SMI), visceral (VAI), subcutaneous (SCAI), and intramuscular adipose (IMAI) indices (cm2/m2), as well as fat-free mass (FFM, kg) and fat mass (FM, kg) were calculated using cross-sectional soft tissue area measurements on pre- and post-CC computed tomography (CT) axial scans and compared using paired Wilcoxon Signed Rank Tests. Results: Median age was 29 years. According to the NHANES FMI-based classification, 5 (26.3%), 9 (47.4%), 4 (21.1%), and 1 (5.3%) patients had normal, excess, class I, and class II obesity, respectively. Median pre- and post-CC BMI was 27.7 vs. 29.6 kg/m2(p = 0.03). Median pre- and post-CC SMI, VAI, SAI, and IAI were 63.5 vs 57.8 (p = 0.14), 19.9 vs 30.8 (p = 0.01), 47.9 vs 58.2 (p = 0.03), and 3.0 vs 5.2 (p = 0.002), respectively. Median muscle density pre- and post-CC were 47.0 vs 43.6 HU (p = 0.002). Pre- and post-chemotherapy FFM were 21.5 vs 19.5 kg, representing an overall median loss of 2.8%, (IQR -10.1, +4.7; Range -49.5 - +16.3; p = 0.14). Conversely, pre- and post-CC FM were 6.6 vs 7.5 kg, representing an overall median gain of 13.3% (IQR -3.3, +17.0; -24.9 - +50; p = 0.01). Median time between imaging assessments was 121 days. Specific median measures of adiposity each increased significantly, such that VIA increased by 29% (p = 0.01), SCAI increased by 39.7% (p = 0.03), and IMIA increased by 39.7% (p = 0.002). Conclusions: While lean muscularity remained stable, we observed significant increases in total body adipose mass with decreased muscle density in this consecutive case series of testicular cancer patients following CC.
Clinical outcomes of minimally invasive retroperitoneal lymph node dissection and single dose carboplatin for clinical stage IIa seminoma.
Authors: Huddart Robert A , Reid Alison Helen , Mayer Erik , Sohaib Syed A , Nicol David
Published: March 2019

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Background: Standard management of Stage 2 seminoma (SEM) is 3 cycles of cisplatin based multi-agent chemotherapy or paraaortic/pelvic radiotherapy. Both treatments have potential short and long term toxicity. We report the use of minimally invasive (robotic or laparoscopic) retroperitoneal lymph node dissection (MI-RPLND) and adjuvant carboplatin. Methods: From 01/2013-04/2017, patients (pt) with SEM and Stage 2a disease on computed tomography (CT) staging scan were considered for MI-RPLND included the radiologically enlarged lymph nodes for Stage 2a SEM. Adjuvant carboplatin (AUC 7) x 1 cycle was administered after confirmation of nodal involvement. Post-operative outcomes including length of stay, Clavien-Dindo 1 complications and pathological staging were recorded. CT was performed at 3 months to verify nodal clearance and then pts monitored with a standard surveillance protocol. Results: Twenty modified unilateral templates were performed. Median and mean post-operative stay was 1 and 1.5 days. One pt required conversion to open surgery and two experienced Clavien-Dindo 1 complications. All pts had preserved ejaculation. Mean number of nodes removed per pt 14.3 (range 5-31) with average 1.75 nodes involved (range 0-5). In 2 pts the enlarged nodes were pN0; they were surveyed and are relapse free at 44+ months. In one case the enlarged lymph node contained embryonal carcinoma (EC) despite primary histology of pure SEM. The remaining 17 pts had confirmed pathological stage 2 SEM. The pt with EC and one pt who had adjuvant carboplatin for stage 1 disease received (B) EP x 2 cycles. 16 patients received a single cycle of adjuvant carboplatin (AUC 7). After median follow-up of 41 months (range 22-70), one patient has relapsed. This occurred at 18 months outside the template of dissection. This patient initially had multifocal disease with 3 pathologically involved nodes. He received BEP X 3 with complete radiological resolution of disease and remains disease free. Conclusions: MI-RPLND in conjunction with a single dose of carboplatin may potentially be an option for the management of Stage 2a SEM. In this series, a subset of pts were overstaged using standard CT imaging.
TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).
Authors: Rini Brian I. , Pal Sumanta K. , Escudier Bernard , Atkins Michael B. , Hutson Thomas E. , Porta Camillo , Verzoni Elena , Needle Michael N. , McDermott David F.
Published: March 2019

541

Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-1 trial in treatment naïve or prior cytokine-treated subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 11.9 months (mos) for T compared to 9.1 mos for sorafenib (S) (p = 0.042, HR = 0.797). However, overall survival (OS) favored sorafenib, likely due to imbalanced crossover to active treatments. TIVO-3 was conducted to confirm the PFS results from TIVO-1. Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. 350 subjects were enrolled to yield 244 events with ~88% power to detect a difference of 6 mos vs. 4 mos with a two-sided p-value of 0.05 by the log-rank test. Secondary endpoints were OS, safety, objective response rate (ORR), and duration of response. Results: The two arms were well balanced for demographics and prior cancer history.60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 28% had prior treatment with a checkpoint inhibitor. T demonstrated a statistically significant improvement in mPFS compared to S, 5.6 (95% CI 7.3-5.3) v. 3.9 mos (95% CI 5.6-3.7; HR 0.73; p=0.02). PFS rate at 2 years was 18% for T compared to 5% for S. ORR was 18% for T compared to 8% for S. 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. Subjects on T were less likely to require a dose reduction (24% v. 38%), interruption (48% v. 63%), or discontinuation (21% v. 29%) due to an adverse event than subjects on S. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this pre-treated population and is better tolerated than S. OS data will be updated prior to presentation. Clinical trial information: NCT02627963.
A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO).
Authors: Powles Thomas , Larkin James M. G. , Patel Poulam , Pérez-Valderrama Begoña , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona , Ralph Christy , Srinivasan Gopalakrishnan , Mendez-Vidal Maria Jose , Liu Wing-Kin , Prendergast Aaron , Vosper Laura , Mousa Kelly , Suárez Cristina
Published: March 2019

545

Background: Metastatic papillary renal cancer (PRC) has poor outcomes and there is need for new treatments. There is a strong rationale for investigating MET and PD-L1 inhibition in this disease. In this study, we investigate savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Methods: This single arm phase I/II trial explored durvalumab and savolitinib at starting doses of 1500mg Q4W and 600mg OD respectively, with a 4wk savolitinib run-in. Treatment naïve or previously treated patients with metastatic PRC were included. Response rate (RR) (RECIST v1.1) was the primary endpoint. Progression free survival (PFS), tolerability (CTCAE v4) and overall survival were secondary endpoints. Biomarkers were explored from archived tissue. Results: Dose escalation work identified a dose of durvalumab of 1500mg Q4W and savolitinib 600mg OD to take forward to phase II. Between Jan 2017 and Jul 2018, 42 patients were enrolled at this dose. 1 patient did not receive study treatment. The following analyses were performed on the remaining 41 patients. 12% of patients did not receive the combination (3 PD, 1 death, 1 PS deterioration). The median follow up was 8.9 months (95% CI: 6.9-10.9 months). IMDC good, intermediate and poor risk disease occurred in 29% (n=12), 63% (n=26), and 7% (n=3) patients respectively. Overall RR was 27% (11/41), while median PFS was 3.3 months (95% CI: 1.5-NR months). RR and median PFS in the previously untreated cohort (N=28) were 29% (8/28) and 12.0 months (95% CI: 1.5-NR months) respectively. Grade 3/4 toxicity occurred in 15 patients. Discontinuation for toxicity occurred in 3 patients, all due to liver toxicities. Biomarker work including PD-L1 and MET expression will be included in the analysis. Conclusions: The combination of savolitinib and durvalumab appears safe and associated with clinical activity in PRC. Clinical trial information: NCT02819596.
Alterations in DNA damage repair (DDR) genes and outcomes to systemic therapy in 225 immune-oncology (IO) versus tyrosine kinase inhibitor (TKI) treated metastatic clear cell renal cell carcinoma (mccRCC) patients (pts).
Authors: Ged Yasser , Chaim Joshua , Knezevic Andrea , Carlo Maria Isabel , Foster Ashley , Feldman Darren R. , Teo Min Yuen , Riaz Nadeem , Lee Chung-Han , Patil Sujata , Chan Timothy An-thy , Hakimi A. Ari , Motzer Robert J. , Voss Martin Henner
Published: March 2019

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Background: Loss of function alterations in DDR genes including core components of mismatch repair and homologous recombination deficiency pathways are associated with tumorigenesis and may determine benefit from IO therapies as shown in colon cancer. The significance for standard IO and TKI treatments in mccRCC is unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for two large cohorts of mccRCC: pts treated with pure IO therapy (cohort 1); and pts receiving first-line TKI (cohort 2). Tumor and germline DNA was subject to targeted panel testing across >400 genes of interest, including 34 DDR machinery genes. Presence of truncating mutations, deletions and functionally validated missense mutations identified individual patient as ‘DDR altered’ (DDRa). Tumor mutational burden (TMB) was inferred for all pts. Non-parametric tests were applied to determine association between DDR status, TMB and treatment outcomes. Results: 225 pts were included (cohort 1=107, cohort 2=118), 37 (16%) were DDRa. Most commonly altered genes were ATM (n=8, 4%) and CHEK2 (n=8, 4%). DDR germline alterations were seen in 12 pts (5%). Median TMB was 4.1 per megabase (range: 0-21.7), and higher TMB (≥ median) was associated with being DDRa (Fisher’s exact, p=0.03). DDRa status correlated significantly with longer overall survival (OS) in the IO cohort (HR 0.29, logrank p=0.04) but not in the TKI cohort (HR 0.74, logrank p=0.44). We found no interaction between objective response and DDR status in either cohort. Conclusions: Loss of function in DDR genes was associated with superior OS in IO-treated but not in TKI-treated RCC pts. Possible underlying mechanisms beyond increase in TMB observed here deserve further study. [Table: see text]
Axitinib versus sunitinib as first-line therapies for metastatic renal cell carcinoma: A multicenter retrospective analysis.
Authors: Hatakeyama Shingo , Tanaka Toshiaki , Ikehata Yoshinori , Fujita Naoki , Masumori Naoya , Kitamura Hiroshi , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: March 2019

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Background: No previous study has compared the efficacy and safety of first-line axitinib and sunitinib. We aimed to compare oncological outcomes and safety of axitinib and sunitinib in patients with treatment-naïve metastatic renal cell carcinoma (mRCC). Methods: We retrospectively evaluated 169 patients with mRCC who were treated with axitinib or sunitinib as the first-line therapy in five hospitals between October 2008 and August 2018.Oncological outcomes and safety were compared between axitinib (n = 68) and sunitinib (n = 101) groups. Inverse probability of treatment weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate effects of first-line therapies on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results: Patients in the axitinib group were significantly older (66 vs 72 years) than those in the sunitinib group. Median relative dose intensity was significantly higher in the axitinib group (94 ± 62%) than in the sunitinib group (65 ± 20%; P = 0.001). Objective response rate was significantly higher in the axitinib group (21%) than in the sunitinib group (10%; P = 0.042). IPTW-adjusted Cox regression analysis revealed significant differences in CSS and OS but not in PFS between the two groups. Safety in terms of grade ≥3 adverse events was significantly different between the axitinib (34%) and sunitinib (55%) groups ( P = 0.006). Conclusions: Compared with sunitinib, axitinib significantly prolonged CSS and OS and showed a safer profile as the first-line therapy for treatment-naïve mRCC.
Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC.
Authors: Rini Brian I. , Appleman Leonard Joseph , Figlin Robert A. , Plimack Elizabeth R. , Merchan Jaime R. , Wang Keshi , Thamake Sanjay , Zojwalla Naseem J. , Choueiri Toni K. , McDermott David F.
Published: March 2019

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Background: The transcription factor hypoxia-inducible factor (HIF)-2α has been established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC) due to underlying VHL deficiency. Activation of HIF-2α can also promote immunosuppression. In preclinical models, HIF-2α inhibition demonstrated increased efficacy in combination with checkpoint inhibitors (Han et al. AACR 2016). In a Phase 1 dose escalation/expansion trial in heavily pre-treated advanced ccRCC patients, PT2385 monotherapy was associated with variability in drug exposure with higher therapeutic exposure associated with improved anti-tumor activity (Courtney et al. JCO 2018). Methods: In the current Phase 1 expansion cohort, patients with advanced ccRCC who had received 1-3 prior therapies (including at least one VEGF(R)-targeting agent) were treated with PT2385 (800 mg PO BID) in combination with nivolumab (3 mg/kg IV Q2Weeks) to evaluate safety, efficacy, and pharmacokinetics. Results: 50 patients were enrolled. Median age was 62 with 58% ECOG 1 and 42% ECOG 2. Median number of prior therapies was 1; 42% of patients received ≥2 prior lines of therapy. The most common all-grade AEs were anemia (46%), fatigue (46%), nausea (36%), and arthralgia (30%). The most common Grade 3 AE’s were anemia (4%), fatigue (4%), and hypoxia (4%). Two Grade 4 events of elevated ALT and increased lipase/amylase were observed. As of August 31, 2018, ORR = 22% (1 CR, 10 PR). At a median follow up of 12.4 months (m), median PFS was 7.3 m for all patients. Patients who had sub-therapeutic exposures ( < 300 ng/ml) of PT2385 (n = 17) had a median PFS of 4.7 m compared to patients with therapeutic exposures of PT2385 (n = 33), who had a median PFS of 10.0 m. Conclusions: The combination of PT2385 + nivolumab was well tolerated and demonstrated promising anti-tumor activity in advanced ccRCC patients, most notably in patients who achieved therapeutic exposure of PT2385. Single agent and combination studies with PT2977, a second-generation HIF-2α inhibitor with an improved PK profile, are ongoing. Clinical trial information: NCT02293980.