bluuebunny/crossref_metadata_2025 huggingface dataset:
Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma (RCC): Updated results from phase I/Ib IVY study.
Authors: Naing Aung , Papadopoulos Kyriakos P. , Wong Deborah J.L. , Aljumaily Raid , Hung Annie , Afable Manuel , Kim Jong Seok , Ferry David , Drakaki Alexandra , Bendell Johanna C. , Tannir Nizar M.
Published: February 2020

679

Background: Pegilodecakin (PEG), a pegylated recombinant human interleukin-10, has demonstrated clinical benefit and manageable toxicity in advanced RCC (Naing et al. 2016 JCO, Naing et al. 2019 Lancet Oncol). As part of the multi-arm (arm A to J) phase 1 IVY study, PEG alone (Part A) or in combination with pazopanib (Part G) or anti-PD-1 (pembrolizumab or nivolumab; Parts H+I) were investigated in heavily pretreated RCC patients (pts). Methods: In a phase 1/1b study which enrolled 353 pts in the US from 2013 to 2017, we analyzed treatment-related adverse events (TRAEs) graded by CTCAE v 4.02, tumor response by irRC, progression-free survival (PFS), and overall survival (OS) for all the advanced RCC pts who received PEG-containing treatment (n=66). Data cut-off was February 19, 2019. Results: Sixty six heavily pretreated RCC pts received PEG alone (n=24, 1-20 µg/kg), with pazopanib (n=4, 10µg/kg), with pembrolizumab (n=9, 10-20 µg/kg), or with nivolumab (n=29, 10-20 µg/kg). Most pts were male (70%), median age 62.5 years, initially diagnosed as stage IV (42%) with clear cell histology (64%), ECOG performance status of 1 (58%), and intermediate/poor (73%/14%) risk per IMDC category. Patients received a median number of 2 prior therapies. Most common grade 3/4 TRAEs were anemia (32%), thrombocytopenia (15%), and hypertriglyceridemia (14%). No pts died due to a TRAE. Median follow-up was 31.5 months. Conclusions: PEG alone or in combination with anti-PD-1 or pazopanib suggested some clinical activity with manageable toxicity in advanced RCC pts. These findings support further ongoing studies of PEG combinations in RCC pts. Clinical trial information: NCT02009449 .[Table: see text]
Epidemiology and regional variation in the mortality of patients admitted with prostate cancer in the United States.
Authors: Mariam Roy Arya , Konda Manojna , Goel Akshay , Verma Rashmi
Published: February 2020

69

Background: Prostate cancer is one of the most common cancers in men and one of the leading causes of death among men of all races worldwide. Prostate cancer prevalence and mortality vary substantially by race, ethnicity and geography. The reason behind the disparity is unclear, however, access to screening and treatment, variation in exposure to risk factors, genetic susceptibility, lifestyle practices are the suggested factors that affect the disparity. Methods: We conducted a retrospective analysis of the National Inpatient Sample Database for the year 2016. Patients who were admitted with a principal diagnosis of Malignant Neoplasm of Prostate (MNP) were identified using ICD-10 codes. The epidemiology, racial disparities and regional variations in the mortality of prostate cancer, trend in the cost and length of stay were studied. Results: A total of 39,853 hospitalizations were identified with a principal diagnosis of MNP. The prevalence of MNP was found to be 0.56% with mean age of diagnosis 71.36 ± 0.55. The prevalence of prostate cancer was found to be highest in African Americans (0.65%), followed by Caucasians (0.60%). The disease-specific mortality rate for MNP was 3.45% (n=1,375). African Americans (AA) had 32% more risk of dying with prostate cancer when compared to all the other groups (OR= 1.322, P= 0.001, 95% CI= 1.14-1.52). Caucasians had 25% less chance of dying and Hispanic had 28% less chance of dying with prostate cancer when compared to AA (OR= 0.755, P= 0.001, CI= 0.65-0.87 vs OR= 0.72, P= 0.016, CI= 0.56- 0.94). Those who admitted to West were 22% more likely to die and those admitted to Northeast were 18% more likely to die when compared to Midwest and south regions (OR= 1.22, P= 0.037, CI= 1.01- 1.47 vs OR= 1.18, P= 0.062, CI= 0.91-1.4). The length of stay and also cost of stay were found to be highest for African American population. Conclusions: The prevalence, mortality of prostate cancer, cost and length of inpatient stay were highest among African Americans. There was a statistically significant difference in the mortality rate of prostate cancer based on the hospital regions in the United States. More studies are needed to better understand the reasons behind the regional difference.
Clinical outcomes of metastatic renal carcinoma following disease progression to programmed death (PD)-1 or PD-L1 inhibitors (I-O): A Meet-URO group real-world study (Meet-Uro 7).
Authors: Santini Daniele , Stellato Marco , De Giorgi Ugo , Pignata Sandro , Pantano Francesco , De Lisi Delia , Casadei Chiara , Maruzzo Marco , Naglieri Emanuele , Buti Sebastiano , De Vivo Rocco , Di Lorenzo Giuseppe , Sbrana Andrea , Soraru' Mariella , Fornarini Giuseppe , Mucciarini Claudia , Grillone Francesco , Roviello Giandomenico , Vignani Francesca , Procopio Giuseppe
Published: February 2020

691

Background: In metastatic renal cell carcinoma (mRCC), immune-oncology (IO), alone or in combination, (IO-IO or IO-TKI) has changed the therapeutic scenario. Few real-world data are available about safety and outcome after IO progression. Methods: Baseline characteristics, outcome data including progression-free survival (PFS) and toxicities were retrospectively collected from 162 eligible pts treated in 16 Italian referral centers adhering to the Meet-Uro group and progressing to IO. Results: 111 pts (68,5%) were treated after progression to IO. 142 (87.6%) pts received IO as second line, 5 pts as first line and 16 pts as further line. Subsequent therapy included cabozantinib (n = 79, 48.0%), everolimus (n = 11, 6.7%), sunitinib (n = 6, 3.7%) and others (n = 15, 9.25%). Median IO-PFS was 4 months (95%CI 3.1-4.8) with no difference in pts pretreated with pazopanib or sunitinib (4 months (95%CI 2.4-5.5) vs 3,9 months (95%CI 2.9-4.9) p = 0.5). PFS tends to be longer in pts reporting adverse events of any grade (5.03 (95%CI 3.8-6.1) vs 2,99 (95%CI 2.4-3.5) months p = 0.004) or without nephrectomy (4.1 vs 2.9 months p = 0.071). Median PFS, in pts treated post-IO, was 6.5 months (95%CI 5.1-7.8). In term of best response, 55 pts (49%) had stability of disease/partial response and 29 pts (26%) had progressive disease, for the other pts treatment is still ongoing. Pts with ECOG PS 0 at progression to IO, had longer PFS, 11 months (95%CI 5.7-17.5) as well as those treated with cabozantinib (7.6 months, 95%CI 5.2-10.1) compared to everolimus, (3.2 months, 95%CI 1.8-4.5) or other drugs (4.3 months, 95%CI 1.3-7.4) p = 0.001. All grade adverse events were reported in 83 pts (74%) with G3-G4 adverse events in 39 pts (35%). Median overall survival, from first line, was 41,1 months (95%CI 30.4-51.8). Conclusions: In our real world experience after progression to IO, most pts received VEGF-TKI and mTOR inhibitors that showed to be active and safe choices. Cabozantinib was associated with a longer mPFS.
Occurrence of tyrosine kinase inhibitors-induced renal impairment and its predictive value for the prognosis of patients with metastatic renal cell carcinoma.
Authors: Zhang Haoran , Zhang Xingming , Zhu Xudong , Zeng Hao , Li Zi , Shen Pengfei
Published: February 2020

693

Background: To investigate the tyrosine kinase inhibitors (TKIs) related renal impairment (RI) on the therapy efficacy and survival of patients with metastatic renal cell carcinoma (mRCC). Methods: Clinical and pathological parameters of patients with mRCC treated with TKIs were retrospectively reviewed. Blood urea nitrogen (BUN), proteinuria(PU) and estimated glomerular filtration rate (eGFR) were defined as main renal function related parameters, and their levels at the time of pre- and post- TKIs treatment were recorded and analyzed. Abnormal BUN, PU and/or eGFR were defined as RI. Primary and secondary treatment outcomes were progression-free survival (PFS) and overall survival (OS), and tumor response was defined as secondary treatment outcome. SPSS 24.0 and GraphPad Prism 7.0a were used for statistical analyses. Results: A total of 110 patients were included in this study. At baseline, patients with abnormal BUN, abnormal eGFR and PU were 25 (22.7%), 27 (25.5%) and 30 (27.3%), respectively, which increased to 46 (41.8%), 55 (50.0%) and 64(58.2%) after TKI treatment. Survival analysis showed that baseline RI had no impact either on prognosis, or the effectiveness of TKIs. On the contrary, for post-treatment RI, PU level, elevated PU, and eGFR level were independently related to PFS and OS. Besides, eGFR decrease >10% was indicated for longer OS time (19.0 vs 41.0 months, p=0.034). Sub-analysis suggested that, among 51 patients without RI pre-TKI therapy, eGFR level (P=0.004), eGFR decrease > 10% (P=0.012), PU level (P=0.014) as well as elevated PU level (P=0.006) were statistically correlated with OS time. However, the similar trend was not identified in those with baseline RI. Furthermore, baseline eGFR level (P=0.020) and eGFR decrease > 10% (P=0.016) within 1y after TKI therapy were identified to be effective biomarkers predicting OS. Conclusions: The occurrence of TKI-induced RI was indicated for better tumor response and survival outcomes, and provide valuable information for the individual treatment of mRCC patients. Thus, routinely monitoring of renal function, especially eGFR and PU, was highly recommended in TKIs-treated mRCC patients.
Safety and efficacy of retreatment with immune checkpoint inhibitors (ICIs) in patients with metastatic RCC (mRCC) who have previously received an ICI.
Authors: Ravi Praful , Bakouny Ziad , Flippot Ronan , Braun David A. , Abou Alaiwi Sarah , Wei Xiao X. , McGregor Bradley Alexander , Kilbridge Kerry L. , Choudhury Atish Dipankar , Harshman Lauren Christine , Choueiri Toni K.
Published: February 2020

698

Background: Several ICIs are approved for use in first and subsequent lines of therapy in mRCC, either alone or in combination with another ICI or targeted therapy. There is limited data on whether patients who receive an ICI derive benefit from a subsequent line of ICI-based therapy. Methods: We reviewed mRCC patients at our institution who were treated with an ICI between 2009 and 2018 having previously received ICI-based therapy. The primary outcomes of interest were radiologic response and time to treatment failure (TTF) on ICI retreatment. Immune-related adverse events (irAEs) were graded using CTCAE v5.0. Results: A total of 31 patients were retreated with an ICI, either alone (n=15) or in combination with another ICI (n=8), tyrosine kinase inhibitor (n=2) or investigational agent (n=6); reasons for discontinuation of prior ICI were disease progression (n=23), toxicity (n=7) and study completion (n=1). Median age at the start of first-line therapy was 62 years and the majority of patients (n=30, 90%) had International Metastatic RCC Database Consortium intermediate- or poor-risk disease; median follow-up was 3.4 years (95% CI 2.5-4.6). The median number of lines of therapy received prior to ICI retreatment was 3 (range 1-7). Of 27 evaluable patients, 3 (11%) had a partial response (PR) to ICI retreatment (2 with ICI-ICI combination therapy and 1 with single-agent ICI), 13 (48%) had stable disease, and 11 (41%) had progressive disease (PD) as their best response; of the 3 with a PR, 2 had a PR and 1 had SD to prior ICI therapy. In comparison, 13 of 31 patients (42%) had a PR or better to first ICI-based therapy, with 4 (13%) having PD. Median TTF on ICI retreatment was 3.2 months (95% CI 1.8-5.2), compared to 8.2 months (3.3-10.0) on prior ICI. 19 patients experienced an irAE with ICI retreatment, with 8 (26%) suffering a grade 3 or higher irAE. Conclusions: Retreatment with ICIs after prior therapy with an ICI was relatively safe but demonstrated limited efficacy. Additional data, ideally from prospective studies, assessing outcomes of retreating patients with ICIs are needed to determine whether using different ICIs in sequence has a role in treatment of mRCC.
Optimal sequence strategy with nivolumab and targeted therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Logeart Juliette , Simonaggio Audrey , Elaidi Reza Thierry , Hans Sophie , Thibault Constance , Oudard Stephane , Vano Yann-Alexandre
Published: February 2020

700

Background: Nivolumab is an approved standard tretatment for pts with mRCC after one VEGFR-TKI failure. Some reports suggest that Nibolumab provides similar response rate across treatment line. Nevetheless, no comparative data has been reported on the sequence of 2nd line Nivolumab followed by TKI vs TKI followed by Nivolumab in 3rd or later line. Objective: To determine the optimal sequence of Nivolumab monotherapy and anti-VEGFR-TKI in mRCC beginning from the 2nd line. Methods: We included in a French expert center all patients with mRCC who received real-life experienced of anti-PD1 nivolumab monotherapy in 2nd line setting or later were included in a French expert center. Clinical characteristics were prospectively recorded including IDMC prognostic factors. Patients who did not receive TKI on the 1st line were excluded. Survival outcomes and subgroups analysis were performed using log rank test and univariate cox regression analysis. Results: 91 patients with mRCC received Nivolumab between January 2006 and May 2018, 58 pts received nivolumab in 2nde line (63%) and 33 in 3rd line and more. Median follow-up was 18.9 [0.1;143] months starting from the beginning of the 2nd line. All received first line anti-VEGFR TKI, 83%/11% sunitinib/pazopanib. At the beginning of 2nd line, IMDC prognostic groups were Fav 19%/Int 56%/ Poor 24%, with similar repartition (p=0,8) between pts treated with Nivolumab vs others. PFS at 6 months for 2nd line was in favor of patients treated by targeted treatments with respectively 63% (IC95% [46%;80%]) and 34% (IC95% [23%;49%]), p=0,06. OS at 24 months for 2nd line was significatively higher for patients treated by targeted treatments with 72% (IC95% [56;87%]) and 46% (IC95% [31%;61%]), p=0,007. Conclusions: We report for the first time the optimal timing to sequence Nivolumab – targeted therapy in patients with mRCC. We found better PFS and OS when Nivolumab is given after the 2nde line of treatment. Subgroups analysis including IMDC prognostic groups and duration of fist line TKI will be presented at the meeting.
Differences in the exposure to sunitinib in the immediate and deferred cytoreductive nephrectomy (CN) arms of the randomized controlled trial SURTIME.
Authors: Abu-Ghanem Yasmin , Van Thienen Johannes V. , Blank Christian U. , Powles Thomas , TOMBAL Bertrand F. , Collette Laurence , Haanen John B. A. G. , Bex Axel
Published: February 2020

703

Background: SURTIME compared immediate CN followed by sunitinib 50mg/day (4/2 weeks on-off) 4 weeks after surgery (n=50) versus 3 cycles sunitinib followed by CN in the absence of progression and continued sunitinib 4 weeks after surgery (n=49). In the intention to treat analysis, the hazard ratio of the secondary endpoint overall survival (OS) favored deferred CN [0.57 (CI: 0.34–0.95, p=0.032)] with a median OS of 32.4 (CI: 14.5-65.3) versus only 15.0 months (CI: 9.3–29.5), following immediate CN. We investigated differences in exposure to systemic therapy between the two arms. Methods: Post-hoc exploratory analysis of number of patients receiving sunitinib, overall response rate (ORR) by RECIST 1.1, length of drug exposure and dose intensity in the immediate and deferred arm. Descriptive methods and 95% confidence intervals (CI) were used. Results: In the deferred arm, 97.7% (CI: 89.3-99.6; n=48) received sunitinib versus only 80% (CI: 66.9-88.7, n=40) in the immediate arm. Following immediate CN, 19.6% had confirmed progression at an interval CT scan 4 weeks after CN compared to baseline and 25% started with sunitinib > 4 weeks after surgery. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm versus 32.7% in the deferred arm, who had a per-protocol recommendation against nephrectomy. In the deferred arm, 83% completed 3 cycles sunitinib with 77.1% at >90%-120% relative dose intensity and an ORR of 29%, reducing the median sum of target lesions from 162 to 127 mm prior to planned CN.Of the patients who started with sunitinib in the immediate (n=40) or continued in the deferred arm after CN (n=29) median duration of treatment was 140 versus 351 days. Conclusions: With immediate CN fewer patients receive systemic therapy, which is administered later and shorter compared to the deferred approach. Starting systemic therapy with sunitinib leads to early and more profound control of the disease and identification of progression prior to planned CN which may translate into the observed survival benefit. Clinical trial information: NCT01099423.
Nephrectomy after complete response to immune checkpoint inhibitors for metastatic renal cell carcinoma (mRCC): A new surgical challenge?
Authors: Pignot Geraldine , Thiery-Vuillemin Antoine , Walz Jochen , Lang Herve , Werle Pierre , Balssa Loic , Geoffrois Lionnel , Leblanc Louis , Albiges Laurence , Di Nunno Vincenzo , Bensalah Karim , Ladoire Sylvain , Gravis Gwenaelle , Barthelemy Philippe
Published: February 2020

707

Background: In the current era of Immune checkpoint inhibitors (ICI), the role and timing of nephrectomy in the case of complete response on metastatic sites is still unknown. We aimed to evaluate the feasibility of nephrectomy for residual disease in patients with metastatic renal cell carcinoma (mRCC) and complete response (CR) on metastatic sites following ICI. Methods: Patients who underwent partial or radical nephrectomy after prior ICI between 2015 and 2018 were retrospectively included and clinicopathological data were reviewed. Perioperative data and postoperative outcomes were recorded. Results: Eleven patients without initial cytoreductive nephrectomy at diagnosis underwent delayed nephrectomy after long ICI administration because of complete response on metastatic sites. Median age was 59.8 years [38-67]. All patients had clear cell RCC on the initial biopsy. IMDC prognostic group was intermediate (81.8%) or poor (18.2%). ICI was administered as first-line therapy in 36.4% of cases (4/11) and as second-line option after TKI in 63.6% of cases (7/11). Treatments regimens were: nivolumab + ipilimumab (n = 3), nivolumab + tivozanib (n = 2) or nivolumab alone (n = 6). The median duration of ICI treatment was 10 months (range: 3-38 months) and the mean number of cycles was 27 (range: 6-75). Median operative time was 243 minutes [135-345] and mean blood loss was 909 cc [40-4000]. In 81.8% (n = 9) of the cases, surgeons experienced challenges for finding dissection planes due to inflammatory infiltration. The 30-day Clavien-Dindo postoperative complication rate was 54.6%, including 1 surgery-related death. Pathological report showed lymphocyte and/or macrophage infiltration in 54.6% and complete pathological response in 2 cases. Median follow-up was 15 months, with 73% of patients free from progression and 54% free from systemic treatment at 1 year. Conclusions: Nephrectomy following ICI for mRCC could allow achieving CR in selected patients. Due to technically complexity and complications rates, this surgery should be performed in centers with extensive experience.
A systematic review and network meta-analysis of first-line treatment options in patients metastatic renal cell carcinoma.
Authors: Riaz Irbaz Bin , Ryu Alexander J. , Yao Yuan , Siddiqi Rabbia , Mathew Jessey , Sipra Qurat Ul Ain Riaz , Zahoor Haris , Wang Zhen , Murad M. Hassan , Pagliaro Lance C. , Costello Brian Addis
Published: February 2020

709

Background: Several immunotherapy (IMT) combinations either as an IMT doublet or IMT in combination with TKIs are now available for first-line therapy of metastatic renal cell carcinoma (mRCC). In the absence of head-to-head clinical trials, we performed an indirect comparison of frontline treatment options to provide clinical guidance. Methods: Medline, Embase and Cochrane Library were searched to identify relevant trials. Hazard ratios (HR) and confidence interval (CI) for primary outcome of progression-free survival (PFS) and secondary outcome of overall survival (OS) were abstracted. Network meta-analysis was performed using a multivariate, consistency model, random-effects meta-regression. Data on Grade 3 or higher AEs was abstracted and meta-analyzed. Pre-specified subgroup analyses were performed based on risk categories (high risk vs low and intermediate vs), history of prior nephrectomy, PD-L1 positivity, age and sex. Risk for bias(RoB) was assessed using the Cochrane Collaboration’s tool. Results: Nine studies were included for PFS analysis, and 6 studies for OS analysis. Avelumab-axitinib (AA) (HR 0.69, 0.48-0.96), and Pembrolizumab-Axitinib (PA) (HR 0.89, 0.50-0.96) significantly improved PFS, while there was no significant PFS benefit with atezolizumab-bevacizumab (AB) (HR 0.83, 0.62-1.13) and nivolumab-ipilimumab (NI) (HR 0.85, 0.63-1.15) as compared to Sunitinib. PA (HR 0.53, 0.38-0.75) and NI (HR 0.63, 0.44-0.90) significantly improved OS, while AB (HR 0.93, 0.75-1.12) showed no significant OS benefit as compared to Sunitinib. NI and AB had significantly fewer grade ≥3 AE than sunitinib. No significant interaction was found by risk group, age, sex or prior nephrectomy. Significant interaction was found by PD-L1 expression(p<0.001), with significant PFS improvement in PD-L1 positive (HR 0.62, 0.53-0.73) but not in PD-L1 negative patients (HR 0.92, 0.81-1.05). Overall, RoB was low amongst included studies. Conclusions: AA improved PFS, NI improved OS, whereas PA improve both PFS and OS as compared to sunitinib monotherapy. However, no IMT combination was superior to other combinations. Cost effectiveness analysis will be reported separately.
Cost-effectiveness of pembrolizumab in combination with axitinib as first-line treatment for advanced renal cell carcinoma.
Authors: Bensimon Arielle G. , Zhong Yichen , Swami Umang , Briggs Allison , Young Joshua , Feng Yuan , Song Yan , Signorovitch James , Adejoro Oluwakayode , Chakravarty Abhiroop , Chen Mei , Perini Rodolfo F. , Geynisman Daniel M.
Published: February 2020

716

Background: Pembrolizumab/axitinib significantly prolonged progression-free survival (PFS) and overall survival (OS) vs. sunitinib in a phase 3 trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib vs. other first-line treatments of advanced RCC from a US payer perspective. Methods: A partitioned survival model with 3 states (progression-free, progressed, death) evaluated costs and quality-adjusted life years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib and pazopanib in the overall population; sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with poor/intermediate IMDC risk. Time on treatment, PFS, and OS were extrapolated using parametric models fitted to KEYNOTE-426 data (24 Aug 2018 cutoff) for pembrolizumab/axitinib and sunitinib, and hazard ratios from network meta-analyses for other comparators. Costs of first-line and subsequent treatment, adverse events, medical resources, and terminal care were estimated based on trial results, drug labels, and published sources. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EQ-5D data. Results: Over a lifetime, the incremental cost-effectiveness ratios (ICERs) for pembrolizumab/axitinib were below willingness-to-pay thresholds of $150,000/QALY or $180,000/QALY (approx. 3 × gross domestic product per capita) vs. all comparators in the overall and intermediate/poor risk populations (table). Results were robust in deterministic and probabilistic sensitivity analyses. Conclusions: Pembrolizumab/axitinib is associated with higher QALYs and considered cost-effective vs. other first-line treatments of advanced RCC in the US.[Table: see text]
Prevention of docetaxel-associated febrile neutropenia with primary granulocyte colony-stimulating factors (GCSF) in Chinese metastatic hormonal-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC).
Authors: Poon Darren M.C. , Chan Kuen , Chan T.W. , Ng Bryan , Siu S Wai-kwan , Ng Joyce , Johnson David , Lee Ka Chai ,   Hong Kong Society of Uro-Oncology
Published: February 2020

72

Background: Plenty reports suggest Asian prostate cancer patients are more susceptible to docetaxel-related febrile neutropenia (FN). However, primary GCSF prophylaxis is currently not recommended by international guidelines for patients with mCRPC or mHSPC when docetaxel is administered. Therefore, we aim to evaluate the potential benefit of primary GCSF in preventing the potentially life-threatening FN for Chinese mHSPC and mCRPC treated with docetaxel. Methods: Two cohorts (2003-2012 & 2015-2018) that consisted of Chinese patients with mHSPC and mCRPC who had docetaxel at six public oncology centres in Hong Kong were grouped and analysed. Primary GCSF was defined as its administration within 5 days of beginning docetaxel, and its use was at the discretion of oncologists. The primary outcome was FN within 21 days of first cycle of docetaxel (1st FN). Multivariable regression analysis was used. Results: A total of 377 metastatic prostate cancer (mHSPC, n=100 (26%); mCRPC, n=277 (73%)) patients with docetaxel treatment was identified. Primary GCSF was given in 71 (18%) patients. The baseline characteristics were balanced between groups with and without primary GCSF. FN was happened in 61 patients (16%), with 37 (9%) of them at 1st cycle. Primary GCSF were administered in 2 and 69 patients with and without 1st FN, respectively (5.4% vs 20.3%, p=0.03). Primary GCSF was associated with reduced risk of 1st FN (odds ratio (OR), 0.22; 95% CI 0.05 - 0.96; p=0.04) in overall, and a similar trend was observed in both mHSPC (OR, 0.36; p=0.35) and mCRPC (OR, 0.16, p=0.08) subgroups. Besides, among various clinical parameters, poor performance status (ECOG 2-3) was associated with increased risk of 1st FN (OR, 3.90, 95% CI 1.66 – 9.13, p=0.002). Conclusions: Primary GCSF prophylaxis is suggested for Asian mCRPC and mHSPC patients, particularly those with poor performance status, to alleviate the risk of docetaxel-related febrile neutropenia.
Investigating the role of the gastrointestinal microbiome in response to immune checkpoint inhibitors (ICIs) among patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Agarwal Anika , Modliszewski Jennifer , Davey Lauren , Reyes-Martinez Marco , Runyambo Daniella , Corcoran David , Dressman Holly , George Daniel J. , Valdivia Raphael , Armstrong Andrew J. , Zhang Tian
Published: February 2020

730

Background: ICIs are effective in mRCC, but one pertinent clinical need is to identify predictive biomarkers for response. The PD-1 receptor has been implicated in regulating gastrointestinal commensal bacteria, with varied immune interactions, thereby impacting response to ICIs. We evaluated bacterial taxa and ICI outcomes in mRCC pts. Methods: Fecal samples from 22 mRCC pts were collected at baseline, week (wk)-4 on ICI, and upon disease progression. Pts were grouped as responders (R, complete or partial response) or non-responders (NR, stable or progressive disease). Microbial DNA was isolated by next generation DNA sequencing. The V4 region of bacterial 16S ribosomal RNA was amplified from extracted DNA and analyzed for bacterial abundance, as well as alpha diversity indices (number of amplicon sequence variants [ASVs], Shannon’s Index, Faith’s Phylogenetic Diversity, and Pielou’s evenness) and beta diversity indices on ASVs (Bray-Curtis, Jaccard, and unweighted/weighted UniFrac dissimilarity measures). Results: Beta diversity analysis at baseline showed no difference in microbial composition between Rs and NRs. However, beta diversity analysis did show a significant change in composition from baseline to wk 4 in R vs NR pts (Bray Curtis p-value=0.03). Among mRCC pts with CR to ICIs, counts of bacteria in the phylum Verrucomicrobia had an upward trend from baseline to wk 4. All mRCC pts with CR (n=3) had Akkermansia at wk 4. However, Akkermansia colonization was not sufficient for response, present in 7/9 Rs and 6/11 NRs. Conclusions: Baseline microbiome differences between ICI Rs and NRs are not enough to predict outcomes. Diversity changes between baseline and wk-4 on treatment could be an early predictor of response. Factors other than presence of Akkermansia (tumor or host-specific, Akkermansia strain variation, or other bacteria in the microenvironment) may contribute to response. Further species and strain-level profiling of the microbiota, tumor-specific genomic alterations, host immune response, and increasing sample size of ICI-treated patients may improve detection of significant differences between Rs and NRs.
Association of modified Glasgow Prognostic Score (mGPS) with survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).
Authors: Brown Jacqueline T , Liu Yuan , Martini Dylan J. , Shabto Julie M. , Hitron Elise , Russler Greta , Caulfield Sarah , Yantorni Lauren Beth , Joshi Shreyas S. , Kissick Haydn , Ogan Kenneth , Carthon Bradley Curtis , Kucuk Omer , Harris Wayne , Master Viraj A. , Bilen Mehmet Asim
Published: February 2020

738

Background: The current risk models for mRCC were developed for patients treated with targeted therapy. The mGPS incorporates albumin and C-reactive protein and may serve as a composite prognostic biomarker in mRCC in the era of CPI. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPI (anti-PD1 or PD-L1 agents) at Winship Cancer Institute between 2015-2018. Overall survival (OS) and progression-free survival (PFS) were defined as months from CPI initiation to death or clinical/radiographic progression, respectively. mGPS was defined as a summary score with one point given for CRP > 10 mg/L and/or albumin < 3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 78 eligible patients were included with a median follow up of 30.7 months. Median age was 66 years (range = 38-82), 64% were male, 78% had clear cell histology, and 76% received anti-PD-1 monotherapy. Higher mGPS at baseline was significantly associated with worse OS while at week 6 was associated with worse OS and PFS (Table). Conclusions: A higher mGPS score in the early course of CPI treatment was associated with worse survival in patients with mRCC. These results should be validated in a larger, prospective study.[Table: see text]
Prognostic value of epithelial-mesenchymal transition markers in clear cell renal cell carcinoma.
Authors: Qu Yuan-Yuan , Tian Xi , Xu Wenhao , Anwaier Aihemutaijiang , Ye Dingwei , Zhang Hailiang
Published: February 2020

739

Background: Epithelial-to-mesenchymal transition (EMT) in important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). Methods: A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. Results: We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Conclusions: Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.
Association of De Ritis Ratio and Neutrophil Lymphocyte Ratio with renal functional decline and all-cause mortality in renal cell carcinoma.
Authors: Keiner Cathrine , Meagher Margaret , Patil Dattatraya , Saito Kazutaka , Patel Devin , Ghali Fady , Dutt Raksha , Miller Nathan , Bradshaw Aaron , Wan Fang , Yasuda Yosuke , Fuji Yasuhisa , Master Viraj A. , Derweesh Ithaar
Published: February 2020

741

Background: We sought to investigate utility of pre-operative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and De Ritis Ratio as predictors of all-cause mortality (ACM) and renal functional decline renal cell carcinoma (RCC). Methods: Multi-institutional retrospective analysis of patients undergoing surgery for RCC. Multivariable analysis (MVA) was conducted to elucidate independent risk factors for ACM, de novo estimated glomerular filtration rate (eGFR)<45 ml/min/1.73m2 and eGFR<30 ml/min/1.73m2. Kaplan-Meier analysis (KMA) was used to investigate ACM, and de novo CKD. Results: 2928 patients were analyzed [1850 Male/1078 Female, median follow up 30.5 months, median tumor size 4.5 cm, 1741 partial nephrectomy (PN)/1187 radical nephrectomy (RN)]. 690 patients had NLR ≥ 3, while 208 patients had NLR ≥ 6; 110 patients had PLR ≥ 3; and 474 patients had De Ritis Ratio ≥ 3. MVA for risk factors associated with worsened ACM showed male sex (OR 1.6, p=0.02), HTN (OR 2.1, p=0.001), increasing tumor size (OR 1.12, p<0.001), clear cell RCC (OR 2.0, p=0.001), RN (OR 1.6, p=0.048), NLR≥ 6 (OR=2.4, p=0.001), Di Ritis Ratio≥3 (OR 2.4, p<0.001), and de novo eGFR<45 (OR=1.6, p=0.015) to be independent risk factors. MVA for factors associated with development of eGFR<45 included increasing age (OR 1.03, p<0.001), male (OR 1.5, p=0.01), HTN (OR 2.3, p<0.001), clear cell RCC (OR 2.2, p<0.001), RN (OR 6.8, p=0.03), NLR≥6 (OR 2.0, p=0.002), and Di Ritis Ratio≥3 (OR 2.3, p<0.001) to be independently associated. Variables associated with development of eGFR<30 included age (OR 1.05, p<0.001), DM (OR=3.01, p<0.001), black race (OR 1.9, p=0.005), Di Ritis Ratio≥3 (OR 2.0, p=0.001), and NLR≥6 (OR 2.1, p=0.002). PLR was not associated with OS, de novo eGFR<45, or de novo eGFR<30. On KMA, NLR≥6 was associated with worse OS (p<0.001). Di Ritis ratio ≥1.5 was associated with worse OS p<0.001 and Di Ritis ratio (≥3) was associated decreased freedom from of de novo eGFR<45 (p=0.026). Conclusions: Elevated NLR and De Ritis Ratio were associated with functional decline and worsened OS, while PLR was not predictive. These markers may be helpful in identifying high-risk patients.
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRP—Early observations of efficacy.
Authors: Liaw Bobby Chi-Hung , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K.
Published: February 2020

89

Background: Optimal sequencing of therapeutic agents in mCRPC remains debated, but the standard approach is to treat with one agent until resistance is met before switching. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat intrinsic heterogeneity, delay/prevent drug resistance, and minimize toxicity. Methods: Enrolled patients all received 3 consecutive treatment modules, each 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month regimen, patients are followed on ADT alone. Primary endpoint for the study is PSA or radiographic time to progression (TTP). Results: From 3/2017 to 10/2019, 35 of 40 planned men with mCRPC were enrolled, 25 patients have completed the 9-month study regimen and evaluable for TTP analysis. With median follow up of 52 weeks, median time to PSA progression after therapy completion is 15.5 weeks (95%CI; 5-26.1+ weeks). PSA response rates show successive improvements with each sequential treatment module (Table). Six (24%) patients continue on post-study surveillance with ADT alone, two of which have remained off any mCRPC agents for over a year (64+ weeks, 54+ weeks). In patients needing to restart therapy, experience with efficacy and tolerability of each agent while on the study, has helped inform subsequent mCRPC drug selection. The study regimen is well-tolerated, with few grade 3/4 AE’s: hyperglycemia (14.3%), diarrhea (5.7%), anemia (2.9%), fatigue (2.9%), neutropenia (2.9%), and thrombocytopenia (2.9%). Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen demonstrates significant antitumor benefits, with potential for long-term suppression of disease. Further longitudinal follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160. [Table: see text]
A prospective phase II/III multicenter study of PSMA-targeted 18F-DCFPyL PET/CT imaging in patients with prostate cancer (OSPREY): A sub-analysis of regional and distant metastases detection rates at initial staging by 18F-DCFPyL PET/CT.
Authors: Pouliot Frederic , Carroll Peter , Probst Stephan , Pienta Kenneth J. , Rowe Steven P. , Saperstein Lawrence , Siegel Barry , Patnaik Akash , Preston Mark A. , Alva Ajjai Shivaram , Gorin Michael A. , Morris Michael J.
Published: February 2020

9

Background: Current imaging modalities are suboptimal for the initial staging of men at risk of harboring occult metastatic prostate cancer (PCa). PSMA-based imaging is considered highly promising for PCa detection. 18F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for positron emission tomography (PET) that may be useful in staging of pts with high risk PCa. The diagnostic performance of 18F-DCFPyL regarding regional and distant metastases has been previously reported. Here we report on detection rates and the resulting impact 18F-DCFPyL may have on staging of pts with high risk PCa. Methods: 18F-DCFPyL PET/CT was evaluated in 252 men with high-risk PCa who were planned for radical prostatectomy with lymphadenectomy (RP-PLND). 9 mCi (333 MBq) of 18F-DCFPyL was administered 1-2 hours prior to PET/CT. Based on TNM staging, 18F-DCFPyL PET/CT detection rates including lesion counts were systematically analyzed: prostatic (T), pelvic LN (N), extra-pelvic LN (M1a), bone (M1b) & other visceral organs/soft tissue (M1c). Three central, blinded, and independent readers evaluated the 18F-DCFPyL scans. Results: At study entry, 97% and 99% of all evaluable pts had no known nodal or metastatic disease, respectively, based on standard cross-sectional imaging. Of these, 18F-DCFPyL PET/CT staged 37 (14.7%) pts with N1 disease and 27 (10.7%) pts with M1 disease (1 [0.4%] M1a, 23 [9.1%] M1b, and 3 [1.2%] M1c). In total, 56 (22%) of patients were upstaged to N1 or M1 disease by 18F-DCFPyL. The positive predictive value of 18F-DCFPyL based on histopathologic validation for pelvic LNs was 86.7% (95% CI: 70, 95). Only one patient in Cohort A underwent a biopsy of their 18F-DCFPyL detected M1 finding; histopathology confirmed the metastatic lesion in the spine to be a true positive. Conclusions: A total of 22% of pts with high-risk PCa planned for RP-PLND had regional or distant metastatic lesions detected on 18F-DCFPyL PET/CT. These results suggest the potential utility of 18F-DCFPyL PET/CT in the staging of men with newly diagnosed high risk PCa to develop optimized treatment paradigms. Clinical trial information: NCT02981368.
Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tran Ben , Horvath Lisa , Dorff Tanya B. , Greil Richard , Machiels Jean-Pascal H. , Roncolato Felicia , Autio Karen A. , Rettig Matthew , Fizazi Karim , Lolkema Martijn P. , Fermin Anthony C. , Salvati Mark , Kouros-Mehr Hosein
Published: February 2020

TPS261

Background: AMG 160 is a novel HLE BiTE immune therapy that redirects T cells to kill tumor cells by binding to PSMA on tumor cells and CD3 on T cells. Methods: Primary objectives of this open-label, ascending, multiple-dose, phase 1 study (NCT03792841) are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 160 in men with mCRPC; secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary efficacy. The dose exploration will estimate the MTD or RP2D by Bayesian logistic regression modeling. The dose expansion will assess safety, efficacy, PK, and pharmacodynamics (PD) of the selected dose and provide further safety and efficacy data. PD biomarkers and potential patient selection biomarkers will be explored. Preliminary antitumor activity will be assessed by objective response per RECIST 1.1 with PCWG3 modifications, PSA response, duration of response, time to progression, PFS (radiographic and PSA)/OS, and circulating tumor cell (CTC) response (CTC0 and CTC conversion). Imaging will include CT/MRI, bone scan, 68Ga-PSMA-11 PET/CT, and 18F-FDG PET/CT. In cycle 1, patients will be pretreated with dexamethasone before short-term IV infusion of AMG 160 and will be hospitalized for 72 h after each AMG 160 dose. Key inclusion criteria: age ≥18 y; histologically/cytologically confirmed mCRPC that progressed after novel hormone therapy; failure of 1–2 taxane-based regimens or have refused a taxane regimen; bilateral orchiectomy or continuous androgen-deprivation therapy; evidence of progressive disease; total serum testosterone ≤50 ng/dL. Key exclusion criteria: active autoimmune disease or diseases requiring immunosuppressive therapy (low-dose prednisone permitted); CNS metastases, leptomeningeal disease, or spinal cord compression; prior PSMA-targeted therapy (177Lu-PSMA-617 may be allowed). The study will enroll 30–50 patients in the dose exploration and 50 patients in the dose expansion globally. The study opened in January 2019; dose exploration is ongoing. Clinical trial information: NCT03792841.
Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response.
Authors: Maughan Benjamin Louis , Nussenzveig Roberto , Swami Umang , Gupta Sumati , Agarwal Neeraj
Published: February 2020

TPS267

Background: RA is a calcium-mimetic radiopharmaceutical emitter of alpha particles that has been approved for treatment of mCRPC. Radiation plus checkpoint inhibitors has demonstrated promising efficacy in previous clinical trials (PMID 27466265, 23535954). Alteration to PD-1 expression has been observed with radium-223, suggesting potential synergy with Nivo (PMID 29137877). ctDNA concentration may accurately reflect overall tumor burden and response to immune therapy. ctDNA testing after 6 weeks of therapy predicts efficacy of immunotherapy in patients with metastatic NSCLC and urothelial carcinoma (PMID 30093454) and metastatic gastric cancer (PMID 30013197). Reduction of ctDNA correlated with both radiographic progression free survival (rPFS) and overall survival. We hypothesize that RA + Nivo will be safe and decrease ctDNA, which may predict response to therapy earlier than conventional scans. Methods: This is a single-arm phase I/II investigator initiated trial (NCT04109729). Primary objectives: 1) Safety, 2) Change in ctDNA after 6 weeks treatment compared to baseline. Secondary objectives: 1) PSA-PFS; 2) PSA 50% response rate; 3) Time to skeletal related event; 4) Bone metabolism marker response. Inclusion criteria: symptomatic bone metastasis, mCRPC, adequate hematopoiesis. Exclusion criteria: visceral metastasis, history of autoimmune disease and current use of immune suppression therapy. A total of 36 patients will be enrolled. Cycles are 28 days. ctDNA concentration will be measured using GuardantOMNI research platform which evaluates 500 genes. Treatment: RA (55 kBq/kg IV) monotherapy lead in for two cycles followed by RA plus Nivo (480mg IV) for an additional 4 cycles. Nivo monotherapy then continues for up to 2 years. ctDNA collected prior to combination therapy and 6 weeks after. Restaging scans done every 2 cycles while on radium-223 and every 3 cycles while on nivolumab. Clinical trial information: NCT04109729.
Incorporating mpMRI and biomarkers in active surveillance protocols: The prospective Stockholm3 Active Surveillance trial (STHLM3AS).
Authors: Lantz Anna , Olsson Henrik , Nordström Tobias , Jäderling Fredrik , Egevad Lars , Annerstedt Magnus , Gronberg Henrik , Eklund Martin
Published: February 2020

TPS379

Background: Level one evidence shows that men with low-risk prostate cancer undergoing active surveillance (AS) with repeated PSA tests and systematic biopsies have low mortality. However, monitoring sometimes misses significant cancer progression and causes patient morbidity. The objective of this study is to evaluate a new proposed protocol for AS using the combination of the Stockholm3 test and MRI targeted biopsies in comparison to conventional follow-up using PSA and systematic biopsies. Methods: A prospective multicenter study with paired design was used to evaluate our proposed protocol (Stockholm3, MRI, targeted biopsies) compared with the conventional protocol according to Swedish National Guidelines (PSA, systematic biopsies) for follow-up of men on AS. The STHLM3 study was performed between 2012-2014. In the study 1 374 men were diagnosed with ISUP grade 1 disease. Out of these, 541 men currently on AS were invited to the STHLM3AS study. Eligible individuals had to be alive without any severe comorbidity, without contraindications for MRI and without a history of initiating prostate cancer treatment. The primary endpoint ISUP grade ≥2 cancer and the secondary endpoint number of performed biopsies will be evaluated using relative sensitivity (RS). At baseline a blood test for PSA and Stockholm3 test as well as a bi-parametric MRI was performed. For men with PIRADS ≥ 3 targeted and systematic biopsies were performed. For men with PIRADS < 3 only systematic biopsies were performed. The study is registered at ClinicalTrials.gov (NCTNCT03956108). Results: 301 men on AS have been included in the study. Since this is a trial in progress, no results will be presented. Conclusions: To our knowledge, this is the largest prospective multicenter study evaluating the performance of MRI for disease monitoring in an AS-cohort. Prediction models using biomarkers and MRI will likely both have an increasing role in the monitoring of AS patients in the future. We hypothesise that the sequential use of first Stockholm3 test followed by MRI will decrease the number of biopsies, while retaining the sensitivity to detect ISUP grade ≥2 cancer compared with using systematic biopsies in all men. Clinical trial information: NCTNCT03956108.