bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of F-18 PSMA PET imaging on clinical decision-making in prostate cancer across disease states.
Authors: Arafa Ali , Jain Aditya , Humphrey Brad , Froelich Jerry , Antonarakis Emmanuel S.
Published: March 2023

63

Background: Piflufolastat F-18 (18F-DCFPyL) PSMA PET imaging was recently approved by the FDA for initial staging, biochemical recurrence (BCR), and restaging of metastatic prostate cancer. Given that the PSMA PET is a next-generation novel imaging modality that carries a higher sensitivity for detecting metastatic disease compared with conventional imaging, we aimed to assess how its integration into clinical care may have impacted the management of patients. Methods: We identified 236 patients who underwent an 18F-DCFPyL PET scan at the University of Minnesota between August 2021 to June 2022. The median PSA at the time of imaging was 1.75 ng/ml (range, 0.02 - 3740 ng/ml). All PSMA PET scans were evaluated by an experienced nuclear medicine physician. Descriptive statistics were used to analyze its impact on the clinical care of 158 patients: 22 for initial staging, 110 with biochemical recurrence, and 26 patients with known metastatic disease. The remaining 78 patients had no information available to assess clinical utility. Results: Metastatic PSMA-avid lesions were detected in 152/236 (64.4%) patients. In patients undergoing initial staging of high-risk prostate cancer, 17/40 (42.5%) patients had metastatic lesions outside the prostate involving 10 regional and 5 non-regional lymph nodes, 1 visceral site, and 10 bone metastases. 17/40 (42.5%) of the scans were unremarkable. 6/40 (15%) had equivocal scan results. For the patients with available clinical information, 12/22 (54.5%) had a change in their treatment plan post-DCFPyL, while 10/22 (45.5%) had no change. In the biochemical recurrence cohort, 93/151 (61.6%) had positive lesions: 28 local recurrences, 47 regional and 22 non-regional lymph nodes, 5 visceral and 28 bone metastases. Equivocal and negative scans accounted for 13/151 (8.6%) and 45/151 (29.8%) cases, respectively. 44/110 (40%) of the patients with clinical information had a change in their treatment plan, while the plan did not change for 66/110 (60%) cases. In patients with known metastatic prostate cancer undergoing restaging, 42/45 (93.3%) had DCFPyL-positive lesions; 12 local recurrences, 20 regional and 16 non-regional, 9 visceral, and 29 bone metastases. Equivocal and negative scans accounted for 2/45 (4.4%) and 1/45 (2.2) of cases, respectively. Only 11/26 (42.3%) of those with clinical information had their tentative treatment plan adjusted post-DCFPyL. No change in the treatment plan was made in 15/26 (57.7%) cases. Conclusions: Integration of the F-18 PSMA PET imaging substantially impacted clinical decision-making, especially for initial staging of high-risk localized disease (treatment change in 55%) and for biochemical recurrence (treatment change in 40%). It remains to be seen if this would translate into superior survival outcomes.
Real world analysis of peritoneal metastasis from renal cell carcinoma: Meet-Uro 27 study.
Authors: Stellato Marco , Buti Sebastiano , Maruzzo Marco , Fotia Giuseppe , Sorarù Mariella , Bassanelli Maria , Maiorano Brigida Anna , Grillone Francesco , Galli Luca , Filippi Roberto , Fanelli Martina , Dionese Michele , Maffezzoli Michele , Vincenzi Bruno , Procopio Giuseppe , Verzoni Elena
Published: March 2023

638

Background: Peritoneal metastases (PM) have been reported in approximately 1% of patients (pts) with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe RCC pts with PM treated as per clinical practice. Methods: Baseline characteristics and outcome data of pts with PM from RCC were retrospectively collected from 12 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to September 2022. Results: We collect 91 RCC pts with PM. 87/91 pts received systemic treatment, 4/87 only best supportive care. First line treatment included TKI and ImmuneOncology(IO)-TKI with different Objective Response Rate(ORR) (41% vs 53.8%, respectively) and Disease Control Rate (DCR) (57.1% and 80.7%, respectively) as well as median PFS (9.9 mo (95%CI 4.5-15.4) for TKI and not reached (NR) for IO-TKI (69.7% pts were free from progression at a median follow up of 13.8 months). Primary refractory (PR) pts were 35.7% for TKI and 7.7% for IO-TKI. According to IMDC score, mPFS was consistent among risk categories, 36.8 mo (95%CI 9.6-63.9) for good risk pts, 13.8 mo (95%CI 8.8-18.8) for intermediate pts and 2.9 mo (95%CI 2.2-3.7) for poor risk pts. Synchronous PM was associated to shorter mPFS 11.0 (95%CI 3.1-19.0) compared to patients with metacronous involvement as well as ORR (31.3%) and DCR (43.1%) whereas PR was higher (34.7%). Only 43/87 pts (45.7%) received a second line treatment that was TKI ( ORR 30.7%; DCR 61.5%; or IO (ORR 20.6%; DCR 41.3%). mOS was 21.8 mo (12.0-31.5) for TKI and NR for pts treated with IO-TKI (80.8 alive at 1 yrs). According to IMDC score, mOS was NR for good risk pts, 24.6 (95%CI 15.8-33.3) and 3.4 (95%CI 2.4-4.3) for intermediate and poor risk, respectively. Conclusions: We report one of the largest case series regarding PM from RCC. Poor risk patients according to IMDC score, sarcomatoid feature and liver metastasis were more represented in our population, compared to historical control, suggesting a more aggressive behavior of PM mRCC. Outcome data suggest that TKI-IO as first line treatment, compared to TKI monotherapy, and TKI as second line, compared to IO, are more active treatment for these pts with dismal prognosis. Nevertheless, synchronous PM has been reported in 57% of pts with poorer outcome and lower response rate. [Table: see text]
Real-world treatment patterns and progression-free survival among patients with metastatic castration-resistant prostate cancer: Examining the benefits of sequential androgen receptor pathway inhibitor use.
Authors: Patel Jeetvan , Sawhney Amrita , Byrne Clare , Tang Jackson , Yu Channing
Published: March 2023

64

Background: Numerous treatments with different mechanisms of action are approved for metastatic castration-resistant prostate cancer (mCRPC), but real-world studies increasingly indicate that androgen receptor pathway inhibitors (ARPIs) are the most common treatment choice at both first- (1L) and second-line (2L). Nonetheless, robust evidence on the clinical effectiveness of ARPIs when used sequentially is lacking. The aim of this study was to examine the real-world treatment patterns and associated progression-free survival (PFS) among patients with mCRPC in the United States (US). Methods: This retrospective cohort study used Flatiron Health electronic health record data from 01/01/2013 to 06/30/2020. Included patients were male, aged ≥18 years, had a confirmed diagnosis of mCRPC within the study period, and received ≥1 systemic therapy post-mCRPC diagnosis. Three treatment subgroups were examined, with ARPI defined as abiraterone or enzalutamide: all 1L ARPI users; all 2L ARPI users irrespective of 1L therapy; and 1L ARPI users who received another ARPI at 2L. Treatment patterns were evaluated descriptively; time to next therapy (TTNT) was measured from the start of the ARPI of interest to the start of the subsequent line of therapy. The Kaplan-Meier method was used to evaluate PFS from the start of the ARPI therapy of interest until progression or death from any cause. Results: The study included 2,588 patients (mean age 72 years). ARPIs were the most prescribed systemic therapy in both the 1L and 2L settings: 63% (1,634/2,588) and 46% (808/1,760), respectively. Among 1L ARPI patients, 28.9% received 2L ARPI, 14.0% 2L taxane, 14.3% 2L combo therapies, and 32% received no further therapy. The median TTNT was 7.6, 6.2, and 5.1 months for 1L ARPIs, 2L ARPIs among all users, and 2L ARPIs among patients who received 1L ARPIs, respectively. The corresponding median PFS was 6.5 months, 4.5 months, and 3.9 months, respectively. Conclusions: Among real-world mCRPC patients in the US, ARPIs remain the most common therapy at both 1L and 2L. However, sequential ARPI use appeared to provide diminishing returns, with a PFS of <4 months seen at 2L in those who had received 1L ARPIs. [Table: see text]
Utilization of local treatment modalities and surveillance in veterans with early stage renal cell carcinoma.
Authors: Kumar Abhishek , Salama Joseph Kamel , Boyer Matthew J
Published: March 2023

643

Background: Surgery represents the standard treatment for early stage renal cell carcinoma (RCC). For older patients, especially those with comorbidities including chronic kidney disease (CKD), there have been efforts made to spare renal function. The objective of this study was to evaluate the disease and treatment characteristics of Veterans with early stage RCC. Methods: We used the national Veterans Affairs’ Corporate Data Warehouse (CDW) database to identify patients diagnosed between 2000-2018 with early stage (cT1-2N0M0) RCC. Laboratory and diagnosis data were used to calculate creatinine clearance and Charlson comorbidity score. Chronic kidney disease (CKD) was defined as creatinine clearance < 60 milliliters per minute. The odds of receiving surveillance were evaluated with multivariable logistic regression. Results: Overall 19,555 Veterans with early stage RCC were included. The median age at diagnosis was 65, 90% range (48-82). 9,807 patients (50%) had at least 1 comorbidity and 4169 (21%) had multiple. Of 16,514 (84%) patients with available lab data, 1,359 (8%) patients had CKD. The treatments received were radical nephrectomy (RN) (N=4107, 21%), nephron sparing surgery (NSS) (N=5008, 26%), thermal ablation (N=489, 3%), and surveillance (N=9946, 51%). Compared to 2000-2010, from 2011-2018, there was a higher proportion of patients receiving NSS (29% vs. 20%, p < 0.01) and a lower proportion receiving surveillance (49% vs. 54%, p < 0.01). On multivariable logistic regression, predictors of receiving surveillance included older age (Odds Ratio [OR] 1.03 per year, p<0.01), T1 disease (OR 1.18, 95% CI 1.08-1.28), increasing number of comorbidities (OR 1.12 per comorbidity point, 95% CI 1.08-1.16), or CKD (OR 1.25, 95% CI 1.12-1.41). Compared to creatinine clearance before diagnosis, the median change in creatinine clearance at least 1 year after diagnosis was -46 for RN, -9 for NSS, -8 for ablation, and -24 for surveillance (p<0.01). Conclusions: A significant proportion of Veterans with early stage RCC undergo surveillance. Nephron sparing treatments are becoming increasingly common and are associated with more modest reductions in renal function than radical nephrectomy or surveillance. Further studies are warranted to assess the impact of surveillance on survival and cancer related outcomes.
Real-world survival outcomes of patients (pts) treated with 6-weekly pembrolizumab 400mg (pem6w) plus axitinib (axi) for advanced renal cell carcinoma (aRCC).
Authors: Ansel Sonam , Stares Mark , Jones Robert J. , Symeonides Stefan N. , Manson Laura , Ray-Chaudhuri Anirban , Randhawa Manreet , Slater Sarah , Devasar Abeera , Malik Jahangeer , Sundaramurthy Aravindhan , Elliott Tony , Venugopal Balaji
Published: March 2023

645

Background: The Keynote 426 trial demonstrated 3-weekly pembrolizumab 200mg (pem3w) plus axi twice daily is effective in aRCC. We previously reported real-world experience of pem6w + axi demonstrating a comparable safety profile to pem3w + axi reported in Keynote 426, with the added benefit of less frequent hospital visits. Here we present updated results on progression free survival (PFS) and landmark analyses of overall survival (OS) at 6, 9 and 12-months. Methods: Electronic medical records of pts on pem6w + axi between 1st May 2020 & 1st June 2021 in two large cancer centres in Scotland were analysed retrospectively for pts’ characteristics, efficacy and treatment related adverse events (TRAE). A data cut-off of 1st June 2022 was applied. Results: A total of 93 pts were identified (baseline demographics previously reported). 74 pts (80%) had clear cell histology, 19 pts (20%) had non-clear cell and 11 pts (12%) had sarcomatoid component. Approximately half had previous nephrectomy (46 pts). 15 (16%), 46 (50%) and 32 (34%) pts respectively were classified as favourable, intermediate, and poor risk group as per international metastatic renal cell carcinoma database consortium (IMDC) criteria. The median follow-up was 13 months (inter-quartile range [IQR] 8-17). At data cut off, 59 (63%) had progressed or died, with median PFS of 10.7 (IQR: 4.6-not reached) months. At landmark time-points of 6, 9 and 12 months 63 (68%), 50 (54%) and 42 (45%) of pts were progression free (Table). The median OS was not reached and follow up continues. At landmark time-points of 6, 9 and 12 months 88 (95%), 69 (74%) and 65 (70%) of pts were alive (Table). Clinician assessed radiological response was evaluable in 87 pts. Overall response rate (ORR), including partial response and complete response, was noted in 51 pts (59%). Clinical benefit rate including pts with ORR and stable disease was seen in 74 pts (85%). 82 pts (88%) had any grade and 28 pts (30%) had grade 3/4 TRAE. Any grade immune related AE (irAE) occurred in 62 pts (67%) and grade 3/4 in 19 pts (20%); g3/4 transaminitis (10%), colitis (8%), nephritis (2%) and skin (2%). Any grade AE due to axi occurred in 69 (74%) and grade 3/4 AE in 14 pts (15%). 25pts (27%) on Pem and 19pts (20%) on axi discontinued treatment due to TRAE. Conclusions: Our real-world experience demonstrates that pem6w + axi appears to have comparable efficacy and safety profile to pem3w + axi reported in Keynote 426 study. [Table: see text]
Adjuvant immunotherapy for patients with renal cell carcinoma at increased risk of recurrence following resection: A National Cancer Database analysis.
Authors: Garg Harshit , Bhandari Mukund , Noel Onika , Dursun Furkan , Liss Michael A. , Kaushik Dharam , Pruthi Deepak K , Svatek Robert S. , Ramamurthy Chethan , Mansour Ahmed M
Published: March 2023

649

Background: Radical nephrectomy is the standard management for locoregional renal cell carcinoma (RCC); however, patients with adverse pathological features are at increased risk of recurrence. IMmotion010 and KeyNote 564 trials investigated the adjuvant role of immune checkpoint inhibitors (ICI) for high-risk clear cell RCC (ccRCC) and have yielded conflicting results. We aimed to investigate real-world survival outcomes associated with the adjuvant use of ICI in high-risk ccRCC using the National Cancer Database Methods: In this nationwide contemporary cohort study, patients with newly diagnosed non-metastatic high-risk clear cell RCC undergoing radical nephrectomy between 2015-2019 were included. High-risk RCC was defined as cT2 with Fuhrman grade 4 or cT3a with Fuhrman grade 3/4 or cT3b/T3c/T4 with any grade, or TxN+ any grade. Patients receiving adjuvant ICI were classified as Group A and patients who did not receive adjuvant ICI were classified as Group B. Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) between the groups and cox proportional hazard models were utilized to identify the predictors for OS. Results: Overall, 768 patients met the inclusion criteria; 270 patients in Group A and 498 patients in Group B. The mean age was 60.5(10.6) years, and 70.8% of patients were males (Table). The use of ICI in the adjuvant setting for high-risk RCC increased from 17.4% in 2015 to 61.8% in 2019. The unadjusted and IPW-adjusted Kaplan Meier 5-year overall survival was similar in the two groups [Unadjusted: 36.8% in Group A vs 50.1% in Group B, p=0.30 and adjusted: 39.5% in Group A vs 47.9% in Group B, p=0.17]. The use of adjuvant ICI did not appear to be an independent predictor for OS on multivariable cox regression analysis (HR=1.14, p=0.31) Conclusions: Adjuvant ICI therapy in non-metastatic high-risk ccRCC might not be associated with a benefit in overall survival. [Table: see text]
Impact of systemic therapy (ST) on deferred cytoreductive nephrectomy (CN) perioperative outcomes: A National Surgical Quality Improvement Program (NSQIP) analysis.
Authors: Dason Shawn , Sheetz Tyler , Ray Shagnik , Zimmerman Danielle Elise , Yin Ming , Folefac Edmund , Mortazavi Amir , Gong Michael , Shabsigh Ahmad , Singer Eric A.
Published: March 2023

650

Background: Management of metastatic renal cell carcinoma (mRCC) is highly individualized and often involves cytoreductive nephrectomy (CN) and systemic therapy (ST). The optimal sequencing of CN and ST is uncertain. A difference in perioperative outcomes based on sequence of CN and ST could influence decision-making. We conducted this NSQIP analysis to assess whether preoperative systemic therapy adversely impacted perioperative outcomes in patients receiving deferred CN. Methods: This analysis was conducted using the American College of Surgeons NSQIP Participant Use Data File for years 2019 and 2020. These years were selected because data on receipt of preoperative therapy is only available since 2019. Inclusion criteria were i) CPT code consistent with nephrectomy, ii) urologist operating surgeon & iii) presence of disseminated cancer. All cases with ICD-10 diagnosis codes not consistent with mRCC were excluded. Groups were stratified by their receipt of preoperative systemic therapy within 90 days before CN and we assessed 46 preoperative and perioperative outcomes. Results: The study cohort included 505 patients with 115 (23%) who received preoperative ST. No differences were noted in perioperative outcomes (Table). Patients receiving preoperative ST were more likely to be on steroids (23% vs. 7%, p<0.01) and develop urinary tract infections (4.3% vs. 0.5%, p<0.01). There were no significant differences noted in other related variables like surgical site infections, wound dehiscence, sepsis, septic shock, pneumonia, cardiovascular complications, preoperative hypertension, or preoperative diabetes (p>0.05). Conclusions: Because preoperative ST did not have an appreciable impact on deferred CN perioperative outcomes, decision making for ST and CN sequencing should not be influenced by perioperative outcomes. Those who undergo deferred CN are unlikely to experience delayed time to surgery or perioperative complications from their ST. [Table: see text]
An evaluation of current practice patterns for patients with renal cell carcinoma.
Authors: Boehmer Leigh , Wood Laura S. , Mohs Jocelyn , Liatis Andrea Ines , Vogel Wendy , Matta Maria , Shivakumar Latha
Published: March 2023

655

Background: First-line immunotherapy and tyrosine kinase inhibitor (TKI) treatment combinations have significantly improved clinical outcomes for patients with renal cell carcinoma (RCC). To maximize clinical benefit of these regimens, risk stratification should guide treatment selection and treatment-related adverse events (AEs) should be appropriately managed. The goal of this project was to identify current practice patterns regarding treatment selection, guideline-based management of AEs, care coordination, and patient education for individuals with RCC treated in community oncology programs and practices. Methods: In July-September 2022, ACCC administered an online survey to evaluate current practice patterns for patients with RCC treated in community cancer programs. To maximize participant engagement, the survey was also shared with advanced practitioner, pharmacist, and oncology nurse members of the Advanced Practitioner Society for Hematology and Oncology (APSHO) and the Kidney Cancer Association who provide care to patients with RCC. Results: Respondents (n=104) were mainly surveyed from community cancer care programs or private/physician practices (69%) in urban/suburban settings (90%) who average 25-75 patients with RCC annually (77%). Most respondents (89%) reported using a combination of an immunotherapeutic and a TKI as initial treatment for advanced clear cell RCC while only 61% of respondents reported frequently using risk scores for newly diagnosed patients. 45% of regimen-specific patient education happens as a separate visit, usually conducted by the oncologist (23%) or the infusion nurse (22%), and 37% of respondents conduct this education on the first day of treatment. The responsibility of providing comprehensive patient education seems to vary by program with the oncologist being the most reported (23%), followed by infusion nurse (22%), clinic nurse (20%), advanced practice provider (18%), and pharmacist (16%). The frequency of monitoring AEs differed based on the given regimen. Respondents mainly (54%) monitored on day 1 of the cycle and again mid-cycle in patients receiving immunotherapy, while 40% monitor only on day 1 of the cycle in patients receiving single-agent TKIs. Clinic nurses are primarily responsible (40%) for monitoring treatment adherence in patients receiving TKIs and also triage for associated AEs. Conclusions: This survey has identified real-world practice patterns related to the management and monitoring of patients with RCC prescribed immunotherapy and tyrosine kinase inhibitor combinations. Opportunities exist to increase utilization of risk assessments, create patient education materials for the multidisciplinary cancer care team, and address the optimal frequency of adverse event monitoring.
A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC).
Authors: Shah Neil J. , Campbell Matthew T , Mao Shifeng S. , Ornstein Moshe Chaim , Haas Naomi B. , Gao Xin , Hammers Hans J. , Keshava-Prasad Holavanahalli , Yan Hongxia , Esquibel Vanessa , Geller Robert B. , Beckermann Katy
Published: March 2023

666

Background: Activation of the GAS6/AXL pathway promotes tumor cell proliferation; high levels of GAS6 and AXL have been associated with drug resistance and decreased survival. Batiraxcept is an ultra-high affinity decoy protein that captures GAS6, preventing it from activating AXL signaling. Serum soluble AXL (sAXL)/GAS6 ratio correlates with response to batiraxcept in advanced ovarian cancer. Batiraxcept in combination with cabozantinib is being evaluated in patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) in this study. Prior studies of cabozantinib in similar pt populations have shown an overall response rate (ORR) ranging from 15 – 32.5% and progression-free survival (PFS) from 3.7-7.2 months (mo). Methods: Key eligibility criteria include previously treated ccRCC pts, excluding prior cabozantinib. Objectives were to determine the safety of batiraxcept plus cabozantinib 60 mg, the recommended phase 2 dose (RP2D), ORR, PFS, duration of response. Correlative endpoints included assessment of baseline serum sAXL/GAS6 with ORR and PFS. Results: In Phase 1b (P1b), 26 pts received at least one dose of batiraxcept with cabozantinib (16 pts - 15 mg/kg; 10 pts - 20 mg/kg). Median age was 60 (range 40-81), male 85% (n=22), IMDC intermediate/poor risk 77% (n=20). All pts received prior immuno-oncology (IO) therapy, 54% (n=14) also received VEGF-TKI; 85% (n=22) received 1 to 2 prior lines of therapy (range 1-6). Median follow-up time was 11.6 mo (range 3.7-18). The RP2D is 15 mg/kg. Related adverse events (AE) any grade and grade ≥ 3 were 100% and 39% (n=10), respectively. Cabozantinib dose reductions occurred in 54% (n=14). AEs of special interest were grade 1 or 2 infusion related reactions, 27% (n=7). Batiraxcept was discontinued due to disease progression 62% (n=16) or toxicity 12% (n=3). The table shows P1b efficacy, ORR of 42%, median PFS of 9.3 mo, and DCR of 84%. Twenty (77%) pts had high baseline sAXL/GAS6 levels; ORR was 55% (11/20) with mPFS of 9.3 mo, compared to 0% ORR and mPFS 6.4 mo in the low sAXL/GAS6 pts. Conclusions: Batiraxcept was well tolerated when combined with cabozantinib. No new safety signals were noted. Efficacy for the combination is encouraging compared to historical cabozantinib monotherapy data. Higher GAS6 levels were predictive for treatment response. The P2 accrual is complete and efficacy data are maturing. A P3 trial plans to evaluate the efficacy in ccRCC patients who have progressed on IO-based and VEGF-TKI therapies. Clinical trial information: NCT04300140 . [Table: see text]
A phase II study to evaluate the safety, pharmacodynamics and efficacy of entinostat in combination with nivolumab plus ipilimumab in patients with renal cell carcinoma previously treated with nivolumab plus ipilimumab or nivolumab alone.
Authors: Pili Roberto , Adra Nabil , Logan Theodore F. , Burney Heather , Atkins Michael B.
Published: March 2023

668

Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we opened a Phase II clinical study with the HDAC inhibitor entinostat and the immune check point inhibitors nivolumab (nivo) and ipilimumab (ipi) in clear cell RCC pts previously treated with nivo + ipi or nivo alone. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a dose de-escalation, two stage, phase II clinical trial with a safety lead-in. Due to a funder decision, enrollment was halted after completion of accrual to the safety lead in group. Pts received oral entinostat at a dose of 5 mg (dose level 1) or 3 mg (dose level 2) every 7 days, continuously, with nivo at a dose of 3 mg/kg mg IV every three weeks in combination with ipi at a dose of 1 mg/kg every 3 weeks X 4 doses. Then, nivo 480 mg was continued every 4 weeks. Results: A total of 12 pts with prior nivo+ipi or nivo treatments was enrolled. Dose level 1 (5 pts enrolled) was completed with the following DLTs: thrombocytopenia, nausea and vomiting, pneumonitis. Seven pts were enrolled on dose level 2 which was established as the recommended phase II dose. The most common treatment-related toxicities were fatigue, hypophosphatemia, neutropenia and thrombocytopenia. All were transient. Most of the pts had 2 or more prior treatments. Four pts achieved a partial response, with 3 out 4 pts previously treated with nivo alone (ORR 33%; 95% CI 9.9-65.1). The median PFS was 11.1 months (CI 1.3-26.4). We collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and nivo+ ipi is relatively well tolerated and may be active in pts with RCC. Clinical trial information: NCT03552380 .
Impact of pre-existing anemia and/or packed red blood cell transfusion prior to Radium-223 administration on oncologic outcomes.
Authors: Pierro Michael , Nelson Ariel Ann , Xie John , Jang Albert , Bylow Kathryn A. , Barata Pedro C. , Lawton Colleen Anne , Kilari Deepak
Published: March 2023

67

Background: Radium-223 (Ra-223), a targeted alpha-emitting radiopharmaceutical approved for the treatment of metastatic prostate cancer (mPC), can cause myelosuppression. In the ALSYMPCA trial 30% of patients developed cytopenias, including 13% with grade 3/4 anemia. Therefore, it is recommended that only men with a hemoglobin ≥10 g/dL, platelet count ≥100,000/mm3, and ANC ≥1,500/mm3 be considered for Ra-223. Since the FDA approval of Ra-223 in 2013, several new treatments have been approved for men with mPC. With the changing therapeutic landscape, we anticipate more patients (pts) will have preexisting cytopenia prior to Ra-223 consideration. Hence, clinicians are increasingly likely to face the dilemma of whether it is safe and efficacious to administer Ra-223 in the setting of Hgb ≤10 with/without RBC transfusion support. Methods: We retrospectively identified pts with mPC treated with Ra-223, including a subset of men with Hgb <10g/dl at the Medical College of Wisconsin and Tulane Cancer Center from 2014 – 2019. Clinical data including demographics, prior cancer treatments, laboratory data, blood product transfusion data, and oncologic outcomes were collected. Survival was estimated using Kaplan-Meier method and statistical analysis was conducted using student’s t-test. Results: Sixty-two pts were identified. Median age at the time of Ra-223 was 75.3 years. Of these, nearly 20% (n=12) had a Hgb <10 g/dL and/or received RBC transfusions to meet “eligibility criteria” prior to beginning Ra-223 treatments. Compared to men who had Hgb >10g/dL, men with Hgb <10g/dL required more RBC transfusions both during and after Ra-223 treatment and had significantly worse oncologic outcomes. No patients experienced treatment delays of more than 1 week. There were no significant differences in the median number of treatments prior to Ra-223, median number of Ra-223 treatments received, platelet count nadir, or ANC nadir. Conclusions: Pre-existing Hgb < 10 g/dl and/or RBC transfusions prior to Ra-223 therapy is associated with worse oncologic outcomes in mPC, suggesting that the benefit of Ra-223 is limited in this subset. A larger sample size is needed to further validate our findings. Multivariable analysis is planned. [Table: see text]
Safety and tolerability of pembrolizumab/axitinib combination in metastatic renal cell carcinoma (mRCC): A multicentric prospective analysis (ProPAXI study).
Authors: Guida Annalisa , Maruzzo Marco , Lai Eleonora , Bimbatti Davide , Pierantoni Francesco , Dionese Michele , Fornarini Giuseppe , Zanardi Elisa , Murianni Veronica , Caserta Claudia , Mosillo Claudia , Calandrella Maria Letizia , Sirgiovanni Grazia , Calabro Fabio , Cerbone Linda , Caffo Orazio , Galli Luca , Bracarda Sergio
Published: March 2023

688

Background: Pembrolizumab/axitinib (PAXI) combination is an approved option as first-line therapy of mRCC. The aim of this analysis is to evaluate safety profile of PAXI combo in the real-world experience in Italy. Methods: This is a prospective study including patients (pts) diagnosed with mRCC who received PAXI as first-line therapy in recruiting Italian Centers. Safety data about clinically significant adverse events (AEs), defined as AE requiring corticosteroids, hormone replacement, drug delay, discontinuation or dose reduction were collected. Results: Data from 122 pts treated from January 2021 to September 2022 have been analyzed. With a median follow-up of 10 mos (range 0.2 - 21) and treatment interruption in 35 pts (29%), at landmark 6-mos and 12-mos the treatment was ongoing in 76% (95%CI 0.67-0.83) and 66% of pts (95%CI 0.56-0.75) respectively. In 11% of pts a starting dose of Axi <5mg was reported (8% higher starting dose). 2% of pts experienced Axi dose titration while 37% of pts had a dose reduction. Pts completed a mean of 10 (1 - 31) cycles of Pembro. Toxicity led to treatment discontinuation in 20% (7/35) of cases. Clinically significant AEs occurred in 61% of pts (74), managed with corticosteroids use in 32% (24/74) of pts, hormone replacement (mainly levothyroxine) in 11% (8/74), drug delay in 64% (47/74), discontinuation in 41% (30/74) or dose reduction 18% (13/74). When required, the most used steroid was prednisone (48%) following by dexamethasone (22%), prednisolone (17%), methylprednisolone (13%). Grade 3-4 clinically significant AEs occurred in 25% (18) and 3% (2) of pts respectively, with hepatic injury 33% (6/18) and hypertension 17% (3/18) as the most common reported G3 events. The two G4 AEs reported were pancreatitis and hepatic injury. No treatment-related deaths emerged. In 20% of cases AE were related to Pembro and in 47% of cases to Axi, in 14% to both drugs. In 28% of pts (34/122) a second clinically significant AE occurred, requiring corticosteroids 27% (9/34), hormone replacement 9% (3/34), drug delay 59% (20/34), discontinuation 41% (14/34) or dose reduction 21% (7/34). Grade-3 clinically significant AEs occurred in 29%, with hepatic injury and hypertension (both 3 pts) as the most common events. No grade 4 AEs were reported. The second AE in 21% of cases was related to Pembro and in 59% of cases to Axi, in (9%) to both drugs. Conclusions: PAXI combination had a tolerable safety profile in mRCC, with few high-grade clinically significant AEs, no new toxicities were identified.
Adjuvant immunotherapy in renal cell carcinoma: A living systematic review and network meta-analysis (NMA).
Authors: Sipra Qurat Ul Ain Riaz , Riaz Irbaz Bin , Naqvi Syed Arsalan Ahmed , He Huan , Siddiqi Rabbia , Islam Mahnoor , Asghar Noureen , Ikram Waleed , Xu Wenxin (Vincent) , Singh Parminder , Ho Thai Huu , Bilen Mehmet Asim , Zakharia Yousef , Bryce Alan Haruo
Published: March 2023

694

Background: The treatment landscape of localized renal cell carcinoma (RCC) is rapidly evolving. Recent trials have demonstrated contrasting efficacy with adjuvant immunotherapy. Therefore, we sought to assess the mixed treatment comparisons among different adjuvant treatment options using updated data from trials and quantified the absolute effect with these treatments stratified by risk categories. Methods: This living network meta-analysis was conducted using the living interactive evidence (LIvE) synthesis framework. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each risk category. Results: This NMA included eight RCTs with 8480 participants and seven unique treatment options. Pembrolizumab (pembro; rank 1) was associated with improved disease-free survival (DFS) when compared to atezolizumab (atezo; rank 6; hazard ratio: 0.68; 0.49;0.93), and nivolumab-ipilimumab (nivoipi; rank 5; 0.68; 0.48-0.97). However, no statistically significant difference was observed between pembro and atezo for overall survival (0.53; 0.28-1.01). Survival data for nivoIpi was not reported. No new statistically significant differences were observed since last update. The absolute benefit of atezo and nivoipi was minimal with higher T and N patients (Table). The results were similar with increasing Leibovich risk scores. Conclusions: Current evidence favors the use of a risk adapted approach when offering adjuvant immunotherapy. Adjuvant pembrolizumab remains a preferred treatment in patients with RCC who underwent nephrectomy. [Table: see text]
Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis.
Authors: Zakharia Yousef , Singer Eric A. , Acharyya Satwik , Garje Rohan , Joshi Monika , Peace David J. , Baladandayuthapani Veera , Laancette Claudia , Kryczek Ilona , Zou Weiping , Alva Ajjai Shivaram
Published: March 2023

696

Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .
Creatinine to cystatin C ratio and mortality in renal cell carcinoma.
Authors: Schmeusser Benjamin , Ali Adil , Patil Dattatraya H , Midenberg Eric , Nabavizadeh Reza , Ogan Kenneth , Master Viraj A.
Published: March 2023

697

Background: Creatinine and cystatin C are routinely used to assess renal function. Given creatinine originates from skeletal muscle and cystatin C is produced by nucleated cells, a creatinine to cystatin C ratio (Cr/Cys-C) may positively correlate with muscle mass. Low Cr/Cys-C has also been associated with decreased overall survival (OS) in cancer, including in a combined cohort of genitourinary malignancies. Furthermore, elevated cystatin c has been associated with shorter OS and recurrence free survival (RFS) in renal cell carcinoma (RCC). Cr/Cys-C may be a simple and affordable tool to assist with patient-specific risk stratification. We assess the ability of Cr/Cys-C to predict OS and RFS in patients with RCC. Methods: Retrospective review of a prospectively maintained database identified patients that underwent partial or radical nephrectomy for RCC from 2018-2021. Included patients had preoperative creatinine and cystatin C and 1+ year of follow up. Cr/Cys-C associations with patient/tumor characteristics were determined by generalized chi-square or Fisher’s exact tests for categorical variables and Wilcoxon rank-sum test for continuous variables. Cr/Cys-C ability to predict OS and RFS was analyzed with Kaplan-Meier method and Cox hazards models. Statistical tests were two-sided with type I error set at 0.05. Results: 219 patients were identified. Median age was 64, with most being male (67%). 62% and 29% of patients were white and black, respectively. Median eGFR was 72mL/min/1.73m2. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). 55% were stage T3-T4, with 12% N1 and 16% M1 at time of surgery. 72% had clear cell histology. Low Cr/Cys-C was significantly associated with older age, males, Eastern Cooperative Oncology Group score ≥ 1, radical nephrectomy, T3-T4 stage, and metastasis. Kaplan-Meier curves showed low Cr/Cys-C association with decreased OS (p=0.0003) and RFS (p=0.0094). Cox regression analysis revealed lower Cr/Cys-C as independent predictor of decreased OS (binary HR=3.66, 95% CI 1.2-11.3, p=0.02; continuous HR=0.05, 95% 0.0-0.8, p=0.03) and RFS (binary HR=4.8, 95% CI 1.6-14.6, p=0.006; continuous HR=0.02, 95% 0.0-0.3, p=0.006;Table). Conclusions: Lower Cr/Cys-C may be associated with decreased OS and RFS in patients with RCC. [Table: see text]
Genomic alterations in metastatic renal cell carcinoma (mRCC): Impact on survival and clinical outcomes.
Authors: King Jennifer , Hassoun Rebecca , Althouse Sandra K. , Fausel Christopher A. , Schneider Bryan P. , Logan Theodore F. , Adra Nabil
Published: March 2023

700

Background: Genomic alterations in RCC can serve as biomarkers for response to therapy. Wild type VHL has shown inferior response to VEGF inhibitors, while patients (pts) with mutated VHL have improved outcomes with immunotherapy (IO)/tyrosine kinase inhibitor (TKI) therapy. We describe the impact of genomic alterations on outcomes and response to front-line therapy. Methods: Pts with mRCC who underwent genomic sequencing between 2015-2022 at Indiana University and were treated with front-line therapy were included. Kaplan-Meier method was used to analyze progression free survival (mPFS) and overall survival (OS) using the log rank test to compare groups. Results: 141 pts were included. Median age was 58yrs (range, 24-81). Tumor histology was 68% clear cell, 10% papillary, 9% unclassified, 1% chromophobe, 1% poorly differentiated, and 9% other. 18% of pts had sarcomatoid features; 13% had rhabdoid. 47% pts had metastasis at diagnosis and 53% at relapse. Metastasis sites were lungs 60%, regional lymph nodes (LNs) 41%, bone 36%, distant LNs 21%, liver 17%, and brain 8%. IMDC risk was 18% good, 48% intermediate, 17% poor, and 17% unknown. Front-line therapy was IO/IO in 21%, IO/TKI in 18%, single-agent TKI in 29%, single-agent IO in 6%, and other in 26%. Genetic alterations included VHL in 50%, PBRM1 in 29%, SETD2 in 23%, BAP1 in 16%, and TP53 in 15%. Median follow-up was 2.74yrs (range 0.1-18.6). Overall mPFS with first line therapy was 1.2yrs (95%CI 0.9-1.5). 2-yr OS was 80% (95%CI: 71-86). For pts with a VHL mutation, mPFS was 1.4yrs (95% CI; 0.9-1.8) compared to 0.9yrs (0.5-1.4) for pts without (p=0.38). 2-yr OS for pts with a VHL mutation was 93% (95% CI: 82-97) vs. 68% (95%CI: 54-78) for pts without (p=0.01). No other mutations impacted overall mPFS or 2-yr OS. mPFS for pts treated with IO/IO was 0.6yrs (95%CI 0.3-0.9) vs. 0.9yrs (95%CI 0.5-1.4) for IO/TKI (p=0.09). 2-yr OS for pts treated with IO/IO was 70% (95% CI 44-85) compared to 94% (95% CI 65-99) for IO/TKI (p=0.29). For pts with SETD2 mutations treated with IO/IO, mPFS was 0.7yrs (95%CI 0.3-1.2) vs. 1.4yrs (95%CI 0.8-1.9) for IO/TKI (p=0.01). For pts with BAP1 mutations treated with IO/IO, mPFS was 0.4yrs (95%CI 0.2-1.2) vs. NE (95%CI 0.2-NE) for IO/TKI (p=0.04). The table outlines outcomes by genomic mutation and therapy. Conclusions: VHL mutation was associated with improved 2-yr OS. Pts with SETD2 and BAP1 mutations treated with IO/TKI had improved mPFS, though no differences in OS. [Table: see text]
Clinical outcomes of patients with bone-predominant metastatic renal cell carcinoma.
Authors: Gheeya Jinesh S. , Li Mingjia , Xu Menglin , Zimmerman Danielle Elise , Collier Katharine A. , Wang Peng , Folefac Edmund , Monk Paul , Mortazavi Amir , Clinton Steven K. , Yin Ming , Yang Yuanquan
Published: March 2023

703

Background: Bone-predominant metastatic renal cell carcinoma (mRCC) is associated with aggressive biology and poor prognosis. The optimal management of these patients (pts) remains not well-established. While contemporary trials showed the superiority of immune checkpoint inhibitors (ICI) compared to vascular endothelial growth factor tyrosine kinase inhibitors (TKI), these pts were often excluded due to non-measurable disease. mRCC bone metastases show an enhanced angiogenesis gene signature suggesting the potential for greater responses to TKI. We test this hypothesis in a retrospective study comparing treatment outcomes for the first line (1L) TKI versus ICI in pts with bone-predominant mRCC. Methods: Pts with mRCC who received care at the Ohio State University Comprehensive Cancer Center from 1/1/2008 to 6/1/2021 were identified through retrospective chart review. Bone-predominant metastasis was defined as the number of bone metastases > extra-osseous metastases. Pts who had ≥1 cycle of treatment and follow-up scans were evaluated for treatment responses per RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The comparisons were made between TKI and ICI cohorts, and the significance was determined by logrank test. Pt who received ICI-TKI in 1L were excluded from the survival analysis due to limited N. Results: A total of 335 pts with mRCC were identified, of which 45 (13.4%) had bone-predominant metastasis. Most of the pts (44/45) had clear cell histology. TKI was the 1L intervention for 21 (47%) while 20 (44%) pts received ICI, and 4 (9%) pts received TKI-ICI. TKI and ICI cohorts were similar for International Metastatic RCC Database Consortium (IMDC) Risk (Table). In the TKI cohort, 19 pts had evaluable responses with ORR of 15.7% and SD of 42%. The mPFS was 5.9 months (95% CI 2.8–9), and mOS was 30.4 months (95% CI 3.3–57.6). In the ICI cohort, 16 had evaluable responses with ORR of 6% and SD of 43.8%. The mPFS was 3.4 months (95% CI 0–8.2), and mOS was 19.3 months (95% CI 14.9–23.7). The hazard ratio was 0.58 for PFS and 0.54 for OS, favoring TKI over ICI, although statistical significance was not reached due to the small sample size (p=0.10 and 0.12, respectively). Conclusions: In this single-center retrospective study, pts with bone-predominant mRCC who received TKI compared to ICI as 1L therapy showed improved ORR, PFS, and OS. These results warrant further investigation in larger studies comparing TKI-containing regimen vs ICI doublet. [Table: see text]
Additional biological and clinical characteristics to refine International Metastatic RCC Database Consortium (IMDC) prognostic/predictive assessment in metastatic renal cell carcinoma (mRCC).
Authors: Zampiva Ilaria , Merler Sara , Inzerilli Nicola , Zacchi Francesca , Manduca Stefano , Pafumi Sarah , Piacentini Michela , Marletta Stefano , Cesta Incani Ursula , Torroni Lorena , Vesentini Roberta , Marchetti Pierpaolo , Fantinel Emanuela , Zivi Andrea , Caliò Anna , Brunelli Matteo , Verlato Giuseppe , Milella Michele
Published: March 2023

705

Background: mRCC prognostic stratification is currently based on the IMDC score. However, some patients experience outcomes markedly different from those predicted by the median outcome of their risk class. Moreover, risk scores are prognostic, rather than predictive, and developing reproducible, affordable, biology-based predictive biomarkers to tailor treatment choices in individual pts remains an unmet clinical need. Methods: A retrospective cohort of 113 mRCC pts treated at the Verona University Hospital Trust between 2013 and 2021 was explored to identify additional clinical prognostic factors for OS to complement IMDC score. Outlier pts (i.e. individual pts whose clinical outcome differed significantly from the median of the IMDC group they belonged to) were further explored to find putative molecular signatures, using FISH and IHC assays. Results: At a median follow-up of 69 months (range 18-136m), novel variables impacting on OS in addition to IMDC risk group were identified: bone, central nervous system (CNS) and pancreatic mets and high neutrophil/lymphocyte ratio (N/L) with a cut-off of 3.2. We also analyzed outliers: 3 good-risk pts with lower than expected OS, 4 poor-risk pts with longer than expected OS, and two intermediate-risk pts with long treatment response. Two putative signatures were found predictive of disease behavior: a cold signature (9p loss, poor of TILs) and a hot signature (rich in CD56+, CD15+ and CD8+ infiltrating cells). The cold and hot signatures were found in good risk pts with bad OS and poor-risk pts good OS, respectively; both intermediate-risk pts had a hot signature, consistent with their disease course. Conclusions: Additional clinical and molecular factors have been identified to possibly improve IMDC prognostic performance; multivariable models including them along with standard IMDC are being developed. Molecular analysis suggests potential signatures to be applied in routine clinical practice, whose predictive performance could be validated in prospective multicentric trials. [Table: see text]