bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug-drug interactions (DDIs) in elderly patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib within the multicenter prospective trial ZEBRA/Meet-URO 9.
Authors: Mattana Alvise , Del Re Marzia , Bimbatti Davide , Buti Sebastiano , Claps Melanie , Di Napoli Marilena , Fratino Lucia , Santini Daniele , Sorarù Mariella , Grillone Francesco , Mazzaschi Giulia , Maruzzo Marco , Pierantoni Francesco , Ballestrin Melissa , De Toni Chiara , Lai Eleonora , Dionese Michele , Zagonel Vittorina , Basso Umberto
Published: March 2023

648

Background: The oral tyrosine kinase inhibitor Cabozantinib (CABO) is frequently used to treat patients with metastatic RCC. Polypharmacy is common in elderly pts, thus several drug-drug interactions (DDIs) with cabozantinib may ensue. Methods: ZEBRA /MEET-URO 9 was a prospective, real world trial enrolling pts ≥ 70 years with mRRC treated with CABO at 13 Italian Oncology Centers. All concomitants drugs administered to pts were collected and categorized according to active principles and indication. DDIs were identified through a dedicated software (Lexicomp), scientific databases (Sider4.1) and published articles. Results: we enrolled 104 pts, median age 75.8 years (range 70.2-87.4 yrs). Overall, 91.4% of the cohort was treated at a reduced dose either upfront or due to side effects. Pts took a median of 6 concomitant drugs (IQR: 4-9), for a total of 131 active principles. Software analysis identified 4 DDIs (warfarin, apixaban, diltiazem and furosemide); whereas scientific reports allowed us to identify 15 additional DDIs involving metoprolol, nebivolol, olmesartan, amiloride, simvastatin, rosuvastatin, polyenoic omega-3 fatty acids, loperamide, metoclopramide, metformin, dutasteride, dexamethasone, prednisone, cetirizine and doxazosin. Seventy pts with potential DDIs experienced a trend for higher rate of grade 3-4 adverse events compared to other pts, although difference was not statistically significant (48.7% v 23.5 %, p=0.485). The table summarizes the main DDIs and suggestions to avoid or mitigate their effects Conclusions: the risk of DDIs was not negligible in our cohort of elderly mRCC pts treated with CABO, although the frequent dose reductions of CABO probably confounded their impact on toxicities. Unremitting attention to concomitant medications in the elderly is thus warranted. [Table: see text]
Real-world time-to-castration resistance (CR) among patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) initiating apalutamide (APA), enzalutamide (ENZ), or abiraterone acetate (ABI) from an oncology database.
Authors: Lowentritt Benjamin H , Rossi Carmine , Du Shawn , Muser Erik , Kinkead Frederic , Waters Dexter , Lefebvre Patrick , Pilon Dominic , Agarwal Neeraj
Published: March 2023

65

Background: CR is an important clinical indicator of disease progression and worsening overall survival among pts with mCSPC. This study describes real-world time-to-CR progression in an oncology setting among pts with mCSPC who initiated APA, ENZ, or ABI in the United States. Methods: Clinical data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013 – 07/31/2022) were evaluated. Metastatic pts without evidence of CR before initiating a next-generation androgen inhibitor (AAI) were classified into exclusive treatment cohorts based on the start date (index date) for APA, ENZ, or ABI. CR was identified by a Flatiron algorithm searching for: 1) mention of CR in patient charts, 2) rising prostate-specific antigen (PSA) levels documented from laboratory testing, or 3) mention of rising PSA while on hormonal therapy from unstructured data sources. Pts had ≥12 months (mo) of clinical data pre-index date and were followed from the index date until the end of clinical activity (including death) or data availability. The proportion of pts developing CR was described separately for each cohort using Kaplan-Meier analysis up to 24 mo post-index, with no adjustment for baseline confounders. CR progression rates in the current analysis were descriptively compared to those observed in Phase 3 trials where available. Results: A total of 155 APA, 385 ENZ and 711 ABI pts were evaluated. Mean age at index was ~73 years in each group. Mean follow-up was 12.8 mo (APA), 13.4 mo (ENZ) and 20.6 mo (ABI). Use of androgen deprivation therapy prior to initiation of AAI was observed in ~85% of pts. The median time between documented metastasis and the index date was 2.3 mo (APA), 2.8 mo (ENZ), and 2.3 mo (ABI). Progression rates to CR are shown. By 24 mo, the median time-to-CR was not reached with any treatment studied. By 24 mo, progression to CR was observed in 26% of APA pts in this analysis (32% in TITAN); 36% of ENZ pts in this analysis (25% in ARCHES); and 33% of ABI pts in this analysis (progression to CR not reported in LATITUDE). Conclusions: In this real-world database, the observed proportions of pts progressing to CRPC for the APA and ENZ cohorts were generally consistent with results of Phase 3 trials and include a small proportion of pts with early progression to CRPC. Increased physician awareness of the benefits of early initiation of an AAI along with identification of baseline biomarkers associated with early progression to CRPC may improve clinical outcomes. [Table: see text]
Heterogeneity in physician and patient preferences for the treatment of renal cell carcinoma: Evidence from latent class analysis.
Authors: Vass Caroline , Pinto Cathy Anne , Myers Kelley , Imai Kentaro , Bussberg Cooper , Bhattacharya Rituparna , Calhoun Shawna R , Poulos Christine
Published: March 2023

661

Background: To inform shared decision-making, it is important to learn how patients or physicians trade off the features of adjuvant treatments and whether there is heterogeneity within preferences. Methods: An online discrete-choice experiment survey was administered to patients with physician-confirmed renal cell carcinoma (RCC) and physician-defined intermediate high/high risk of recurrence and physicians who treat such patients. Hypothetical treatment choices were defined by median disease-free survival (DFS); 5-year overall survival (OS) rate; mode and frequency of administration; need for concomitant daily pill; treatment duration; and the risks of severe diarrhea, fatigue, and dizziness. After making an adjuvant treatment choice, respondents were presented with the opportunity to opt out of treatment. Patient and physician choice data were analyzed separately using latent class (LC) models, which identify clusters within patients and physicians making similar choices. Each class’ preference weights were used to calculate the conditional relative attribute importance. Results: LC analysis identified three classes among the 250 patients (% respondents) that placed greater relative importance on: 1) 5-year OS and opting into treatment (37.5%), 2) median DFS and opting into treatment (26.9%), and 3) treatment duration and opting out of treatment (35.5%) (Table). Among the 250 physicians, the LC analysis identified three classes that placed greater relative importance on: 1) 5-year OS and recommending treatment (37.5%), 2) median DFS and recommending treatment (37.8%), and 3) not recommending treatment (24.7%). Additionally, each LC analysis showed that the other treatment attributes evaluated were less important, but the importance varied by LC (Table). Conclusions: Heterogeneity in physician and patient preferences for RCC adjuvant therapy was found, highlighting a need for shared decision-making. Discordance within patients and physicians in the propensity to opt out of adjuvant treatment suggests patient-physician dialogue is important. [Table: see text]
Combined alternating sunitinib and bevacizumab in the management of advanced renal cell carcinoma: A phase I/II trial.
Authors: Bazarbashi Shouki , Alzahrani Ahmed M , Aljubran Ali H , Elshenawy Mahmoud Abdelsatar , Mostafa Gad Ahmed , Maraiki Fatma , Alzannan Noura , Elhassan Tusneem , Badran Ahmed Ali
Published: March 2023

665

Background: Tyrosine kinase inhibitors remain a corner stone in the management of metastatic clear cell renal cell carcinoma (RCC). The intermittent schedule of sunitinib with 4 weeks on/2 weeks off could result in a rebound angiogenesis and tumor progression in the 2 weeks rest period. We propose the use of bevacizumab to alternate with sunitinib to attain continuous anti-angiogenesis during sunitinib therapy. Methods: This was a phase I/II design. Patients advanced clear cell RCC were recruited. Sunitinib was given as 50 mg daily on 4 weeks on/2 weeks off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. Bevacizumab starting dose was 5 mg/kg and the dose was escalated to 10 mg if no dose limiting toxicity. Primary endpoints were response rate and progression-free survival. Results: Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose limiting toxicity was found on the 5 mg dose level of bevacizumab. One patient achieved complete response and 12 achieved partial response for a response rate of 52%. At a median follow up was 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median progression-free survival was 16.5 months (95% CI 4.1-28.8), and the median overall survival was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity. The commonest grade 3 or 4 toxicity was thrombocytopenia and lymphopenia each occurring at a rate of 32%, followed by hypertension at a rate of 28% followed by fatigue at a rate of 24%. Conclusions: Continuous angiogenesis blockade by adding bevacizumab to sunitinib 4 weeks on and 2 weeks break regimen in advanced RCC produce significant anti-tumor activity with manageable increased toxicity. Clinical trial information: NCT02919371 .
Adjuvant immunotherapy in renal cell carcinoma: A systematic review and meta-analysis of randomized clinical trials.
Authors: Huang Emily , Riveros Carlos , Ranganathan Sanjana , Klaassen Zachary , Rini Brian I. , Wallis Christopher J.D. , Satkunasivam Raj
Published: March 2023

671

Background: There has been interest in adjuvant immune checkpoint inhibition (ICI) following surgical resection in patients with high-risk renal cell carcinoma (RCC) given high recurrence rates and approvals of ICI in metastatic RCC. The primary objective of this analysis was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with RCC. Methods: This systematic review was performed according to the PRISMA guidelines. The protocol was registered in PROSPERO (CRD42022361599). We searched PubMed, EMBASE, and relevant conference proceedings to identify phase III randomized controlled trials (RCTs) comparing adjuvant ICI versus placebo/observation. The primary outcome of interest was DFS. Results: Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2=64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (HR 0.85, 95% CI 0.69-1.04), there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) or sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). Conclusions: The evidence base to date regarding ICI as adjuvant therapy in RCC is mixed – conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PDL1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.
Impact of number of treatment lines following first-line (1L) immuno-oncology (IO) combination on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Lemelin Audreylie , Ernst Matthew Scott , Wells Connor , Navani Vishal , McGregor Bradley Alexander , Wong Shirley S. , Pal Sumanta Monty , Basappa Naveen S. , Kapoor Anil , Lee Jae-Lyun , Donskov Frede , Li Haoran , Yuasa Takeshi , Chang Rose , Huynh Lynn , Nguyen Catherine , Holub Ashley , Clear Louise , Duh Mei Sheng , Heng Daniel Yick Chin
Published: March 2023

673

Background: Across the world, treatment of patients with mRCC is heterogeneous with different access to treatment sequences and number of lines of therapy (LOTs) employed. For instance, patients receiving first line (1L) nivolumab+ipilimumab (NIVO+IPI) may be offered second-line (2L) and third line (3L) vascular endothelial growth factor receptor targeted kinase inhibitor (VEGFR-TKI), whereas patients receiving 1L pembrolizumab or avelumab in combination with axitinib (IO+AXI) may only receive one subsequent VEGFR-TKI in 2L. We aimed to examine whether these different treatment strategies impact overall survival (OS). Methods: Adult mRCC patients who received at least three LOTs starting with 1L NIVO+IPI or at least two LOTs starting with 1L IO+AXI from the International Metastatic RCC Database Consortium (IMDC) centers were included. Kaplan-Meier analyses were used to estimate median OS (time from 1L to death). Results were stratified by 1L IMDC prognostic risk. Results: Among 128 patients who received at least three LOTs starting with 1L NIVO+IPI (median age 61 years, 77% White, 77% male, 37% from the US), 14% had favorable, 61% had intermediate, and 26% had poor IMDC risk. The most common 2L treatments following 1L NIVO+IPI were sunitinib (38%), cabozantinib (27%), and pazopanib (20%). Among 104 patients who received at least two LOTs starting with 1L IO+AXI (median age 62 years, 75% White, 67% male, 38% from the US), 28% had favorable, 48% had intermediate, and 25% had poor IMDC risk. The most common 2L treatments following 1L IO+AXI were cabozantinib (57%) and sunitinib (10%). Median OS are presented in the table, which suggested no difference in survival for patients who received at least two LOTs starting with 1L IO+AXI compared to patients who received at least three LOTs starting with 1L NIVO+IPI. Conclusions: Treatment for patients with mRCC varies depending on the 1L regimen chosen and by country. Our results demonstrate that, even with potential guaranteed time bias and IMDC imbalances, there is no statistically significant difference in OS for patients who received at least three LOTs starting with 1L NIVO+IPI and patients who received at least two LOTs starting with 1L IO+AXI, suggesting that selecting effective treatments in 1L resulting in fewer LOTs may have similar clinical outcomes as multiple LOTs. [Table: see text]
Adjuvant pembrolizumab (pembro) for renal cell carcinoma (RCC) across UCLA Integrated Staging System (UISS) risk groups and disease stage: Subgroup analyses from the KEYNOTE-564 study.
Authors: Choueiri Toni K. , Tomczak Piotr , Park Se Hoon , Venugopal Balaji , Ferguson Tom , Symeonides Stefan N. , Hajek Jaroslav , Chang Yen-Hwa , Lee Jae-Lyun , Sarwar Naveed , Thiery-Vuillemin Antoine , Gross-Goupil Marine , Mahave Mauricio , Haas Naomi B. , Sawrycki Piotr , Zhang Tian , Xu Lei , Imai Kentaro , Poehlein Christian Heinrich , Powles Thomas
Published: March 2023

679

Background: Adjuvant pembro prolonged disease-free survival (DFS) for patients (pts) with RCC at increased risk of recurrence after nephrectomy in the phase 3 KEYNOTE-564 study (NCT03142334). This post hoc exploratory analysis evaluated efficacy of adjuvant pembro in pt subgroups based on UISS and disease stage. Methods: Pts with histologically confirmed clear cell RCC (pT2, Grade [G] 4 or sarcomatoid, N0, M0; pT3 or pT4, any G, N0, M0; any pT, any G, N+, M0; or M1 NED) were randomly assigned 1:1 to receive pembro 200 mg IV or placebo (pbo) every 3 weeks for ≤17 cycles (~1 y). DFS was assessed by investigator. UISS risk groups were derived retrospectively from TNM stage, Fuhrman nuclear grade, and ECOG PS. UISS groups were intermediate risk (pT2, G4, N0, M0; pT3, G1, N0, M0; or pT3, G2-4, N0, M0, ECOG 0), high risk (pT3, G2-4, N0, M0, ECOG PS 1; pT4, any G, N0, M0; or N1, M0), or M1 NED. Other subgroups were evaluated based on disease stage. Results: Baseline characteristics were balanced within subgroups. Median follow-up was 30.1 mo (range 20.8-47.5). Of 994 enrolled pts, most had UISS intermediate risk (n = 732, 73.6%; pembro n = 359; pbo n = 373); 195 pts (19.6%; pembro n = 100; pbo n = 95) had UISS high risk, and 58 pts (5.8%; pembro and pbo n = 29 each) had M1 NED. In the UISS intermediate risk group, the hazard ratio (HR) for DFS was 0.65 (95% CI, 0.48-0.88; 24-mo rates, pembro: 81.5%, pbo: 72.4%). In the UISS high-risk group, HR for DFS was 0.77 (95% CI, 0.49-1.20; 24-mo rates, pembro: 65.0%, pbo: 55.9%). In the M1 NED group, HR for DFS was 0.28 (95% CI, 0.12-0.66; 24-mo rates, pembro: 78.4%, pbo: 37.9%). DFS by disease stage is in the Table. Conclusions: Consistent with the results of the intention-to-treat (ITT) population, adjuvant pembro prolonged DFS compared with pbo for all subgroups. Results of this exploratory analysis further support the use of adjuvant pembro after nephrectomy as standard of care for pts with RCC at increased risk of recurrence. Clinical trial information: NCT03142334 . [Table: see text]
Phase II multi-center study of sintilimab in combination with axitinib in patients with advanced fumarate hydratase-deficient renal cell carcinoma.
Authors: Zhang Xingming , Liu Haoyang , Zhang Yaowen , Zhao Junjie , Chen Yuntian , Sun Guangxi , Sheng Xinan , Wang Yongquan , Gong Kan , Liu Xiaodong , Huang Rui , Wei Qiang , Li Xiang , Liu Jiyan , Shen Pengfei , Chen Ni , Yao Jin , Liu Zhenhua , Zeng Hao
Published: March 2023

685

Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly aggressive cancer mainly caused by germline or somatic aberrant of FH gene. Unfortunately, there are no standard treatment. Here we report the preliminary results of a phase II study investigating the efficacy and safety of sintilimab in combination with axitinib in patients with FH-RCC. Methods: Patients were treated at mutli-center in hospitals of the republic of China. Eligibility criteria included age ≥ 18 years and newly diagnosed as FH-RCC by FH immunohistochemistry and next-generation sequencing or multiplex ligation-dependent probe amplification. Patients received sintilimab (intravenous injection, every 3 week) in combination with axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary end point was objective response rate (ORR; RECIST v1.1). This study is registered with ClinicalTrials.gov, NCT04387500. Results: Between July 2021 and October 2022, 21 patients were enrolled. At this preliminary analysis (data cutoff, October, 2022), median follow-up was 9 months (0.9-15.2 months). Nineteen patients were available for efficacy assessment. Confirmed complete response rate was 15.8% (3/19), ORR was 63.1% (12/19). Disease-controlled rate (DCR) was 89.4% (17/19). The median of progression-free survival (PFS) was not reached, with a high 12-month PFS rate of 72.3%. All grade and ≥ 3 treatment-emergent adverse events occurred in 95% (20/21) and 23.8% (5/21), respectively. Conclusions: Sintilimab in combination with Axitinib had a manageable safety profile and achieved a promising tumor response rate in patients with advanced FH-RCC. The trial is an ongoing study, with a total of planned 41 patients from 8 sites. The study start date was June 2, 2021. Clinical trial information: NCT04387500 .
The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma.
Authors: Dai Jindong , Hu Xu , Zhang Haoran , Zhang Yaowen , Zhang Xingming , Sun Guangxi , Zeng Hao , Shen Pengfei , Liu Zhenhua
Published: March 2023

686

Background: A subset of patients with metastatic clear cell renal cell carcinoma (ccRCC) might benefit from metastasectomy, while those with metastatic non-clear cell carcinoma (non-ccRCC) might be potential candidates for metastasectomy remains unclear. Methods: From the metastatic RCC database of West China Hospital, a total of 114 patients with confirmed metastatic non-ccRCC were identified. Patients were divided into groups by systemic therapy plus nephrectomy and metastasectomy or systemic therapy plus nephrectomy alone. Clinical outcomes included overall survival (OS) and progression-free survival (PFS). The potential factors predicting clinical benefits from cytoreductive surgery (including nephrectomy and metastasectomy) were also explored using Cox regression and Kaplan-Meier analyses. Results: 100 patients received nephrectomy alone and another 14 patients who underwent nephrectomy and metastasectomy were enrolled in the present study. In addition, total of 19 metastatic lesions were dissected among 14 patients. Compare to patients with systemic therapy plus nephrectomy alone, systemic therapy plus nephrectomy and metastasectomy could significantly improve the progression-free survival (PFS) (27.1 vs. 12.4 months, HR: 0.352, 95%CI: 0.108-1.143, p=0.046). For patients with synchronous metastasis, only systemic therapy plus nephrectomy alone showed an advantage in the PFS (HR: 0.363, 95%CI: 0.179-0.737, P=0.005) and OS (HR: 0.172, 95%CI: 0.080-0.371, P<0.001). And for patients with metachronous metastasis, systemic therapy plus nephrectomy and metastasectomy could improve the PFS (HR: 0.124, 95%CI: 0.016-0.956, P=0.045) and OS (HR: 0.250, 95%CI: 0.059-0.971, P=0.043). None of the patients had any serious (Clavien-Dindo Classification ≥III grade) perioperative complications. Conclusions: Metastasectomy could be one of the optional treatments for patients with metastatic non-ccRCC. For patients with synchronous metastases, only nephrectomy could improve prognosis; however, patients with metachronous metastases might get benefit from metastasectomy.
Impact of sarcomatoid features on treatment outcomes in metastatic clear cell renal cell carcinoma treated with first-line immunotherapy combinations.
Authors: Fitzgerald Kelly N. , Duzgol Cihan , Knezevic Andrea , Shapnik Natalie , Kotecha Ritesh R , Aggen David H , Carlo Maria Isabel , Shah Neil J. , Voss Martin H , Feldman Darren R. , Motzer Robert J. , Lee Chung-Han
Published: March 2023

687

Background: The presence of sarcomatoid features in clear cell renal cell carcinoma (cRCC) has historically been associated with poor response to tyrosine kinase inhibitor (TKI) monotherapy and poor overall survival; however, immunotherapy (IO) combination therapies have shown more promise in treating this variant. Front-line anti-PD-1 based IO combinations used in ccRCC include ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted TKI with a PD-1 inhibitor (TKI/IO). Here, we compare progression-free survival after therapeutic 1st-line (PFS) and 2nd-line (PFS-2) in patients who received IO/IO vs TKI/IO combinations as 1st line treatment for metastatic ccRCC, and test whether the treatment effects differ based on the presence or absence of sarcomatoid dedifferentiation. Methods: A retrospective analysis was performed on patients with ccRCC initiating 1st line combination IO at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020. Patient cohorts were defined by 1st line treatment type: IO/IO or TKI/IO. PFS and PFS-2 were estimated using the Kaplan-Meier method. Restricted mean survival time (RMST) was calculated for PFS and PFS-2 in each 1st line treatment group and modelled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of treatment effect among subgroups, sarcomatoid features (presence/absence) is included in the models and an interaction test is performed. Results: Ninety patients (28 sarcomatoid) received 1st line IO/IO and 83 (17 sarcomatoid) received 1st line TKI/IO. Median PFS time is 6.8 months (95% CI: 4.5, 12.2) for IO/IO and 21 months (95% CI: 15, 25) for TKI/IO, p=0.009. After adjusting for IMDC risk, and after 48 months of follow-up, RMST for PFS was 10 months for IO/IO and 24 months for TKI/IO (p=0.02) and RMST for PFS-2 was 20 months for IO/IO and 23 months for TKI/IO (p=0.24). In the RMST model, the interaction between treatment group and presence or absence of sarcomatoid features is not significant for PFS (0.95) or PFS-2 (0.29). Conclusions: For ccRCC patients treated with 1st line IO/IO or TKI/IO, adjusted RMST for PFS was significantly longer for the TKI/IO group, but there was no statistically significant difference in adjusted RMST for PFS-2. Anti-PD-1-based therapy is an effective approach to treating ccRCC with sarcomatoid features. [Table: see text]
Outcomes of partial nephrectomy for non-metastatic cT2 renal tumors: Results from a Canadian multi-institutional collaborative.
Authors: Bansal Rahul K. , Cassim Raees , Sun Ryan , Mallick Ranjeeta , Finelli Antonio , Tanguay Simon , Drachenberg Darrel E , Pouliot Frederic , Lavallee Luke , So Alan I. , Rendon Ricardo A. , Wood Lori , Kapoor Anil , Lalani Aly-Khan A. , Basappa Naveen S. , Bhindi Bimal , Dean Lucas W. , Bjarnason Georg A. , Breau Rodney H.
Published: March 2023

690

Background: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. Methods: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/- 1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. Results: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 2] vs 8.4 [IQR 2.4], p=0.05), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p<0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.9). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37), lower risk of distant metastasis (HR 0.36, 95%CI 0.15-0.88), better cancer specific survival (HR 0.56, 95%CI 0.18-1.78) and overall survival (HR 0.36, 95%CI 0.11-1.19) and as compared to RN. At 6 months and beyond after surgery, PN patients had less decline in eGFR than RN patients (-16.6 [SD 21.1] vs -24.4[SD 16.2], p=0.0002). Complications rates between PN and RN were (18% vs 9%, p=0.057). Conclusions: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with slightly higher risk of peri-operative complications, better preservation of renal function, and higher risk of local recurrence. The lower risk of distant metastasis and death was likely from residual confounding unaccounted for in the individual patient match. [Table: see text]
Predictive biomarkers for the oncolytic virus, JX-594, through the HIF-dependent interferon beta pathway in metastatic renal cell carcinoma.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Lee Namhee , Oh Keunhee , Ham Won Sik
Published: March 2023

710

Background: Although combination approaches with an immunotherapy are established as the first-line setting in metastatic renal cell carcinoma (mRCC), immunotherapy are only efficacious for a subset of patients. Our group has been working on improving the benefit of immunotherapy using JX-594 (pexastimogene devacirepvec, Pexa-vec) in mRCC. The purpose of this study is to develop predictive biomarker for JX-594 in metastatic clear cell RCC (ccRCC). Methods: Using ccRCC cell lines representative of each four mutations (786-O (VHL mutation), Caki-2 (VHL and PBRM1 mutation), A-498 (VHL and SETD2 mutation), and 769-P (VHL and BAP1 mutation)), four cell line-derived xenograft (CDX) mouse models have been developed. 2-10x106 tumor cells were subcutaneously injected into the right flank of wild-type BALB/c nude mice. When tumors reached >50 mm3, mice were treated with either PBS or 1x107 plaque-forming units of JX-594 by intratumoral injection in day 0, 3, and 6. Interferon beta (IFN-β) expression were measured with qRT-PCR after the JX-594 treatment in 786-O CDX model. Results: All CDX models demonstrated significant decrease in tumor size by the JX-594 compared to control. Most rapid tumor growth was observed in BAP1-deficient xenografts while PBRM1-deficient xenografts demonstrated the slowest growth among four xenografts. The decrease of tumor volume by the JX-594 was most pronounced in BAP1-deficient tumors compared to VHL, PBRM1, and SETD2 mutation tumors. Even after adjusting the relative differences of tumor growth rate in each model, xenografts with BAP1 loss were still associated with significantly better response to JX-594. IFN-β expression significantly decreased in BAP1-deficient tumors compared to other tumors, while the expression level was recovered dramatically after JX-594. Conclusions: BAP1-deficient tumors demonstrated rapid tumor progression while they were most significantly reduced after JX-594. BAP1-deificient tumors had decreased levels of IFN-β expression while it was most dramatically recovered after JX-594, suggesting the mechanism of JX-594 through the HIF-dependent interferon beta induction. This is the first study to elucidate the potential of BAP1 as predictive biomarker for JX-594 and its underlying mechanisms.
Characterization of anti-cancer immune response associated with immune-related adverse events in patients with kidney cancer.
Authors: Kato Taigo , Kiyotani Kazuma , Ishizuya Yu , Yamamoto Yoshiyuki , Hatano Koji , Kawashima Atsunari , Nonomura Norio
Published: March 2023

711

Background: Some reports showed promising clinical efficacy among patients who discontinued immune checkpoint inhibitors (ICIs) due to immune-related adverse events (irAEs). In this study, we aimed to characterize T cell receptor (TCR) repertoire repertoire in peripheral blood mononuclear cells (PBMCs) before and after ICI treatment, and at the onset of irAE for understanding of irAE-provoked anti-cancer immune responses. Methods: We collected metastatic tumor tissues and peripheral blood samples from 54 patients with advanced kidney cancer before anti-programmed cell death protein 1 (PD-1) treatment and 1 month after treatment initiation. Furthermore, we applied a next-generation sequencing approach to characterize TCR repertoires using tumor tissues and PBMCs. Results: The number of irAEs was significantly higher in responder for nivolumab (p < 0.0001). We also confirmed that irAE present patients had better progression-free survival and overall survival when compared to irAE absent patients (p=0.0010 and p=0.011, respectively). TCR repertoire analysis revealed that diversity index for TCR alpha and beta in irAE present patients were significantly decreased at 1 month after nivolumab, indicating expansion of certain T cell clones even in PBMCs after nivolumab. We also examined morishita index to measure T cell similarity between pre- and post nivolumab samples. As a result, irAE present patients had significantly lower similarity than irAE absent patients, indicating a larger change in the T cell clones, and inducing newly expanded T cell clones in post-nivolumab PBMC samples. Importantly, irAE present patients had significantly higher numbers of peripheral T cell clones shared with metastatic tumor-infiltrating T cells than those in irAE absent patients at 1 month after nivolumab (as per the 100 most abundant T cell clonotypes in the peripheral blood; p=0.038). Conclusions: Our findings revealed that a certain number of irAE-provoked T cell clones can also circulate systemically and attack tumor cells in distant regions, leading to durable response in the patients with irAEs.
DNA alterations in papillary renal cancer.
Authors: Jackson-Spence Francesca , Ackerman Charlotte , Szabados Bernadett , Toms Charlotte , Jovaisaite Agne , Gunnell Rachel , Suárez Cristina , Larkin James , Patel Poulam , Valderrama Begoña Pérez , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona C. , Ralph Christy , Srinivasan Gopalakrishnan , Mendez-Vidal Maria Jose , Markovets Aleksandra , Hartmaier Ryan James , Powles Thomas
Published: March 2023

725

Background: The characterisation of DNA alternations in papillary renal cancer (PRC) is unclear. The CALYPSO trial (NCT02819596) prospectively evaluated combination therapy of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) in PRC. The trial showed high response rates (RR) in the MET-driven population. Here we explore the relationship between MET, PD-L1 and TMB in these tumours and the relevance of other biomarkers including PIK3CA, PTEN and KRAS. Methods: FoundationOne analysis from 41 samples of PRC patients enrolled on the CALYPSO trial was performed. The relevance of co-positivity between MET/PD-L1 and MET/TMB as well as analysis of other DNA alterations such as PIK3CA, PTEN and KRAS was explored. Outcome parameters were correlated with RR, PFS and OS. Results: 41% of patients were MET-driven, 66% were PD-L1+ (vCPS≥1) and 3% were TMB >10mut/Mb. Further testing used TMB ≥ median (2.52mut/Mb) 32% of patients were both MET-driven and PD-L1+. 17% of patients were both MET-driven and TMB ≥ median. RR and survival outcomes for combinations are shown in the table. The overall RR in MET driven and non-MET-driven patients was 52.9% and 13%, respectively. The median PFS and OS in the MET-driven group was 12.0 months (95% CI: 2.9-19.4) and 27.4 months (95% CI: 9.3-not reached [NR]), respectively, compared to a median PFS and OS in the non-MET-driven group of 2.7 months (95% CI: 0.5-5.0) and 7.5 months (95% CI: 0.0-16.0), respectively. PIK3CA, PTEN and KRAS mutations occurred in 1, 4 and 2 patients, with RR of 0% (0/1), 25% (1/4) and 50% (1/2), in the PIK3CA, PTEN and KRAS groups, respectively. Conclusions: MET-driven papillary cancers have low mutational burden, but high PD-L1 expression. Small patient numbers limit definitive conclusions, but responses occur irrespective of the immune biomarkers investigated. Other DNA alterations are rare and did not appear to influence outcomes in this cohort. These data support the design of the SAMETA trial (NCT05043090), further investigating the savolitinib and durvalumab combination. [Table: see text]
ECOG score as a barrier for clinical trial eligibility in the patient population with genitourinary cancer: Is it time to adapt this criterion to real-world data?
Authors: Gortzak Uzan Limor , Lapidot Lena , Bader Tzvia , Gaziel Avital
Published: March 2023

78

Background: ECOG score is a common eligibility criteria used in clinical trials (CT). Many CT recruit only patients in good physical condition (ie. minimal comorbidities and good performance status), which may misrepresent the real-world cancer population.This gap may result in safety and effectiveness data that may not be applicable to the real-world patient population. Furthermore, applying strict eligibility criteria augment a barrier for patient accrual to CT. In this study we analyzed the impact of ECOG performance status on Genitourinary (GU) oncology trials eligibility of patients who used the Trialjectory web-based platform. Methods: Trialjectory is an AI- based platform that matches cancer patients to CT based on a patient reported questionnaire that translates to an individual clinical profile. The profile includes disease status and stage, biomarkers, treatment history and comorbidities and demographics. Data from patients with prostate and urinary bladder cancer was analyzed. The number of matched trials per patient was determined based on the patient’s profile, location and travel preference. To assess the impact of ECOG score, we edited the data set to reflect a better performance status per patient. We used a paired samples Wilcoxon test to assess the association between decreasing the ECOG threshold and the number of matched CT. Results: Between May 2021 and August 2022 we analyzed 153 bladder cancer profiles with ECOG=2 and 71 with ECOG=3, and 90 and 27 prostate cancer profiles with ECOG=2 and ECOG=3, respectively. In a multiple regression analysis, high ECOG score was inversely and significantly associated with the number of matched trials per patient in prostate cancer (p=0.009), independent of cancer stage, patient ethnicity and gender; and in urinary bladder cancer (p=0.003), after adjustment for cancer stage, gender and ethnicity. Editing ECOG score from 2 to 1 resulted in a profound increase (233% for prostate cancer patients and 300% for urinary bladder cancer patients respectively) in the number of matched trials per patient, from a median of 3 trials to 7 and from 2 to 6 trials per patient respectively (V = 426, p-value <0.0001 and V = 14, p-value = 0.0002 respectively). Among Bladder Cancer patients, editing the ECOG score from 3 to 2 resulted in an increase of 200%, from a median 1 to 2 matched CT (V = 291, p-value = 0.0002). Conclusions: The results reflect a high magnitude reduction in eligibility for patients with higher ECOG scores. Excluding these patients may result in skewed reporting on effectiveness-toxicity of drugs that may not be applicable for the real-world patient population augmenting a significant barrier for CT accrual amongst the proactive population who seek it.
Prognostic role of geriatric assessment (GA) in patients with metastatic prostate cancer (MPCaP) attended in medical oncology.
Authors: Girones Regina , Arnal Maria , Forcano Silvia
Published: March 2023

90

Background: The Geriatric Assessment (GA) represents the future of the geriatric oncology to reduce toxicities and treatment-related hospitalization in the elderly. It has demonstrated results in predicting chemotherapy feasibility and response to docetaxel in patients with metastatic castration-resistant prostate cancer (MCRPca) (Della pepa). GA has also been explored in patients suitable to oral treatment (ref). In order to understand the prognostic capabilities of GA, we developed this analysis. Methods: All patients with MPCa sent to evaluation for Medical Oncology from January 2020 to August 2022 were analysed. GA was applied to those with 70 years or more. A geriatrician and/or an oncologist performed the evaluation. Informed consent was signed for patients. Ethical committee approved the protocol. Results: 85 patients were sent to Medical Oncology, 40 young (40%), 51 elderly (50%). Median age for young patients was 62 (46-68) and 79 for elderly (70-91). A comparison between populations is shown. This was an observational prospective study involving 51 patients who were 70 years of age or older. We performed GA including five domains and divided our patients into “fit”, “lower frailty,” and “high frailty” using Rockwood frailty scale. The relation between GC group and overall survival was explored. After GA, 26 were fit (51%), 16 had lower frailty (30%) and 10 had high frailty (19%). We found a statistically significant relationship between GA group and overall survival. Fit patients had overall survival of 27,1 months (22,8-31,5) versus 15,1 months (9,7-19,4) for low frailty and 5,6 months (3,2-7,9) for high frailty (p;0,000). Conclusions: Although our analysis has a selection bias as we only explored elderly patients sent to Medical Oncology, we found that a GA may help clinicians to recognize frail patients, and hence to reduce toxicities and early treatment discontinuation. We demonstrate its capability to be incorporated into routine clinical practice. [Table: see text]
Urologic oncology and critical care: What are prognostic factors that correlate with 6-month mortality in patients (pts) with urological tumors referred to intensive care unit (ICU)?
Authors: Zanetta Giulia Kodja , Nassar Jr Antonio Paulo , Dettino Aldo A.
Published: March 2023

91

Background: Defining which oncologic pts actually benefit from ICU admission can be a difficult task. There is a lack of data that consistently support indication and benefit with impact on patient survival when this care is offered. The present retrospective study sought to evaluate prognostic factors related to mortality in 6 months after hospital discharge of pts with urological tumors admitted to ICU at the A C Camargo Cancer Center. Methods: A retrospective cohort study of pts with urological cancers (bladder, prostate, kidney, testicular, and other) admitted to ICU in 2017-2018. We collected the following data to identify possible predictors of 6-month mortality: gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, type of ICU admission (planned or unplanned), clinical stage at diagnosis (locoregional vs. metastatic). All these variables were included in a logistic regression model with mortality at 6 months as the dependent variable. Results: Assessing the medical record of 677 patients, the pts with ECOG grading >2 presented poorer results compared to the ones 0-2, with an Odds Ratio (OR) 5.10 [Confidence Interval 95% (CI) 2.46-11.69]. The urological tumor type did influence the 6-month mortality, with the best results for pts with testicular tumors: OR 0.27 (CI 0.05-0.99) and the worst ones to bladder tumors with an OR 2.35 (CI 1.44-3.87) when compared to prostate tumors. For metastatic diagnoses, as expected, the mortality results appeared to be worse than for pts with locoregional disease, with an OR 4.06 (CI 2.73-6.07). Finally, pts undergoing unplanned hospitalization at ICU, understanding clinical and surgical ones, presented poorer results compared to the elective ones, with an OR 3.22 (2.16-4.84). Conclusions: In this cohort of pts with urological cancers, 6-month mortality was 39%. Performance status, bladder cancer, metastatic disease and unplanned hospitalizations were all associated with increased mortality.
Clinical utility of IDC-P (intraductal carcinoma of the prostate) in the decision making of initial treatment for metastatic hormone-sensitive prostate cancer.
Authors: Naito Yushi , Kato Masashi , Yamamoto Akiyuki , Tsuzuki Toyonori
Published: March 2023

93

Background: In recent years, the usefulness of using androgen receptor axis-targeted agents (ARAT) such as abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer (mHSPC) in the up-front setting has been demonstrated. However, it is still unclear which patients could truly benefit from these treatments. On the other hand, intraductal carcinoma of prostate (IDC-P) is a known poor prognostic factor for prostate cancer patients. In the present study, we investigated the association between the presence of IDC-P and therapeutic response to mHSPC. Methods: This retrospective analysis included 318 patients with mHSPC from thirteen affiliated institutions between 2014 and 2021, and evaluated biopsy specimens for the presence of IDC-P. All patients were grouped by their first-line treatment, either ARAT (n=100, receiving a combination of androgen-deprivation therapy [ADT] and ARAT), or conventional therapy (n=218, receiving ADT with or without standard antiandrogen agents). We compared overall survival (OS) and second progression-free survival (PFS2) between the ARAT and conventional groups according to the presence of IDC-P to evaluate whether presence of IDC-P predicts response to each treatment. The PFS2 was defined as the period from diagnosis of mHSPC to disease progression on second-line therapy or death. Propensity score matching was used for one-to-one nearest neighbor matching in order to minimize the potential effects of selection bias and confounding factors. The clinicopathological variables of patients were well balanced after propensity score matching. Results: Most patients in the ARAT (79%) and conventional therapy (71%) groups were ICD-P positive. In the propensity score-matched cohort, OS and PFS2 of IDC-P positive cases were significantly prolonged in the ARAT group compared to the conventional group (OS: hazard ratio [HR], 0.36; p=0.047; PFS2: HR, 0.30; p<0.001). In contrast, IDC-P negative cases did not show a difference in OS and PFS2 between the ARAT and the conventional groups (OS: HR, 1.09; p=0.920; PFS2: HR, 0.40; p=0.264). Conclusions: The findings highlight a high prevalence of IDC-P among patients with mHSPC and suggest that IDC-P may be a reliable indicator to implement ARAT as first-line therapy.
TALAPRO-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) vs placebo plus ENZA in patients with DDR gene-mutated, metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Agarwal Neeraj , Saad Fred , Azad Arun , Mateo Joaquin , Matsubara Nobuaki , Shore Neal D. , Chakrabarti Jayeta , Chen Hsiang-Chun , Lanzalone Silvana , Niyazov Alexander , Fizazi Karim ,   for the TALAPRO-3 investigational group
Published: March 2023

TPS279

Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) that has shown efficacy in metastatic castration-resistant prostate cancers with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR). ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition may increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness” phenotype. These studies suggest that TALA in combination with ENZA may significantly improve clinical outcomes for men with mCSPC and DDR-HRR alterations. The phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in this setting. Methods: Approximately 550 patients with mCSPC harboring DDR-HRR alterations will be randomized to TALA (0.5 mg once daily [QD]) plus ENZA (160 mg QD) or placebo (once daily) plus ENZA (160 mg QD). Patients will be stratified according to de novo mCSPC vs relapsed mCSPC, high-volume disease vs low-volume disease, where high-volume disease is defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis, and BRCA vs non-BRCA mutational status. Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in at least one of 12 DDR/HRR genes known to sensitize patients to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is radiographic progression-free survival (defined as time to radiographic progression in soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 or in bone per Prostate Cancer Working Group 3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned/ongoing at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. As of 30 September 2022, a total of 319 patients have been randomized in the study. This study was approved by an Institutional Review Board. Clinical trial information: NCT04821622 .