bluuebunny/crossref_metadata_2025 huggingface dataset:
First-in-human safety, imaging and dosimetry of [68Ga]Ga-DPI-4452, a novel CA IX-targeting peptide, in patients with clear cell renal cell carcinoma.
Authors: Hofman Michael S , Tran Ben , Feldman Darren R. , Pokorska-Bocci Anna , Pichereau Solen , Wessen Jonathan , Haskali Mohammad B. , Sparks Richard , Vlasyuk Olena , Galetic Ivana
Published: January 2024

373

Background: Carbonic anhydrase IX (CA IX) is overexpressed in clear cell renal cell carcinoma (ccRCC) and is associated with aggressive tumor behavior, treatment resistance and overall poor outcomes. DPI-4452 is a first-in-class, cyclic peptide that binds with high affinity to CA IX. Radiolabeling DPI-4452 with gallium-68 ([68Ga]Ga-DPI-4452) or lutetium-177 ([177Lu]Lu-DPI-4452) is an innovative, theranostic approach for identifying and treating patients with CA IX-expressing tumors. Compared with existing antibody approaches, a radiolabeled peptide may confer better characteristics for both PET-CT imaging and therapy. This first-in-human study (NCT05706129) is evaluating the theranostic potential of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 in patients with unresectable metastatic ccRCC, colorectal cancer or pancreatic ductal adenocarcinoma tumors. Here we report safety, tolerability, pharmacokinetics, dosimetry and imaging characteristics of [68Ga]Ga-DPI-4452 from the completed ccRCC imaging cohort. Methods: The DPI-4452 peptide contains a DOTA cage and is radiolabelled with [68Ga]Ga. Following intravenous injection of [68Ga]Ga-DPI-4452, patients underwent serial PET-CT imaging, urine and blood sampling to assess imaging characteristics, biodistribution, and dosimetry of [68Ga]Ga-DPI-4452. Patients were followed for 7 days post-injection for safety observations. Results: A mean activity of 185 MBq [68Ga]Ga-DPI-4452 was administered to 3 patients with ccRCC. No clinically significant toxicities were observed. PET-CT images showed rapid and sustained tumor uptake over 4 h, as well as rapid renal elimination. At 1 h, the maximum tumor standardized uptake value (SUVmax) across 36 lesions ranged from 6.8 to 211.6, with a mean of 64.6. Seventeen of these lesions (found in lymph nodes, lung, pancreas, parotid gland and other sites) were not detectable on prior contrast-enhanced CT. OLINDA dosimetry estimates revealed that the organs receiving the highest absorbed doses (mean [SD] mGy/MBq) were stomach wall (0.33 [0.10]), small intestine wall (0.33 [0.08]) and gallbladder wall (0.21 [0.12]), with a mean whole body effective dose of 0.06 [0.02] mSv/MBq. Absorbed doses in the kidney, liver and bone marrow were low. Over 80% of total administered radioactivity cleared from the bloodstream within 1 h. Conclusions: [68Ga]Ga-DPI-4452 provides exceptional images in patients with ccRCC without clinically significant toxicity. Very high SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection for therapy. The tumor retention and rapid elimination support potential of [177Lu]Lu-DPI-4452 radioligand therapy. Clinical trial information: NCT05706129 .
Linear muscle segmentation for metastatic renal cell carcinoma.
Authors: Nicaise Edouard , Schmeusser Benjamin , Ali Adil , Midenberg Eric , Palacios Arnold Raul , Kearns Ethan , Ambadi Sriram , Patil Dattatraya H. , Joshi Shreyas S. , Narayan Vikram M , Psutka Sarah P. , Nazha Bassel , Brown Jacqueline T , Ogan Kenneth , Bilen Mehmet Asim , Master Viraj A.
Published: January 2024

380

Background: Baseline sarcopenia and postoperative changes in muscle mass are independently associated with overall survival in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN). Here we examine the relationship between preoperative (baseline) and postoperative changes in muscle quantity with survival outcomes following CN as determined by linear segmentation, a fast and clinic-friendly tool. Methods: Our nephrectomy database was reviewed for patients with clear cell, papillary, or chromophobe mRCC who underwent CN. Linear segmentation of bilateral psoas/paraspinal muscles was completed for baseline imaging within 60 days of surgery and imaging up to 1 year postoperatively. ANOVA for numerical and chi-square for categorical variables were used to test for differences according to change in linear muscle index (LMI, cm2/m2). Multivariable models estimated COX hazard ratios for cancer-specific survival (CSS) and overall survival (OS). Kaplan Meier curves estimated CSS and OS. Results: From 2004-2020, 190 patients were identified 48 stable LMI (25.3%; <5% change [0Δ]), 54 increase LMI (28.4%; +5% change [+Δ]), and 88 decrease LMI (46.3%; -5% change [-Δ]). Median time from baseline imaging to surgery was 18 days, while time from surgery to postoperative imaging was 119 days. Patients with +Δ had lower baseline LMI than -Δ or 0Δ (28.5 vs. 32.4 vs.32.5 cm2/m2; p=0.003). 0Δ LMI had lower rates of pN1 disease than other groups (27.1% [0Δ] vs. 42.6% [+Δ] vs. 45.5% [-Δ]; p=0.019). No other differences in pathology were noted. Median CSS and OS were highest among patients with 0Δ LMI (CSS: not reached [0Δ] vs. 61.9 [+Δ] vs. 37.4 [-Δ] months; p=0.0018 || OS: 67.2 [0Δ] vs. 48.5 [+Δ] vs. 26.4 [-Δ] months; p=0.0007). Median follow-up was 56 months for survivors. The table lists factors associated with increased risk of cancer-specific mortality. Conclusions: Change in muscle mass after CN, as measured by the linear muscle segmentation technique, is independently associated with OS and CSS in patients following CN. Of note, lack of change demonstrated greatest survival, potentially secondary to high baseline muscle mass. [Table: see text]
Erectile function in patients with metastatic renal cell carcinoma treated with first-line therapy.
Authors: Tsimafeyeu Ilya , Zukov Ruslan , Borisov Pavel S. , Leonenko Valentina , Kuznetsov Vladimir , Bondarenko Anastasia , Tishova Yulia
Published: January 2024

383

Background: Sexual activity is an important part of social functioning and quality of life. Cancer diagnosis and concomitant treatment has a damaging effect on sexual function. The objective of this prospective study was to evaluate the incidence of erectile dysfunction (ED) in men with metastatic renal cell carcinoma (mRCC) receiving first-line therapy. Methods: All patients were evaluated for erectile function with the 5-item version of the International Index of Erectile Function (IIEF-5) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) before first and after four cycles/months of the first-line therapy with nivolumab plus ipilimumab (IO-IO), pembrolizumab plus axitinib/lenvatinib (IO-TKI) or sunitinib, pazopanib and cabozantinib (TKI). Results: Two hundred eighty-two male patients with mRCC were enrolled. Median age was 60.5 years (range 39–71 years) and 164 (58%) patients had at least one cardiovascular risk factor. Sixty-seven (24%) patients had favorable IMDC risk, 208 (74%) had ECOG ≤1, 214 (76%) had ≥2 organs with metastases, and 11 (4%) had non-clear cell mRCC. All patients were treated with IO-IO (32%), IO-TKI (26%), and TKI (42%). At baseline, IIEF-5 mean score was 17 (SD, 2.9) in ITT population. Patients with 2 and more IMDC risk factors had a lower IIEF-5 mean score (13; SD, 1.4). 182 (64.5%) patients reported a negative change in their sexual life since the start of the therapy. 90 (32%) patients had no sexual activity. After four treatment cycles/months IIEF-5 mean score reduced to 9 (SD, 3.5), which was statistically significant (P<0.0001). The IIEF-5 scores were associated with type of anticancer treatment, with the minimal change observed in IO-IO group (P=0.2) and highest change in TKI group (P<0.0001). A correlation was no found between FKSI-19 and IIEF-5 scoring systems. Conclusions: A prospective assessment in a large group of male mRCC patients revealed mild ED (17/25) in previously untreated patients and moderate ED (9/25) after four cycles/months of first-line therapy, especially in patients receiving TKIs. These changes did not correlate with kidney symptom index.
Association between SPECT/CT total tumor volume (TTV) and new lesions (NLs) in early cycles of 177Lu-PSMA-617 (LuPSMA) and progression-free and overall survival (PFS and OS) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Demirci Ridvan Arda , Gulati Roman , Nelson Peter , Cheng Heather H. , Hawley Jessica E. , Yezefski Todd , Haffner Michael C. , Montgomery Robert Bruce , Schweizer Michael Thomas , Yu Evan Y. , Chen Delphine L , Iravani Amir
Published: January 2024

40

Background: LuPSMA is a newly established treatment in patients with mCRPC, but PSA and survival outcomes vary widely, and predictors of treatment responses are needed. LuPSMA delivers radiation to tumor tissues that can also be imaged with SPECT/CT which provides semiquantitative estimates of TTV and identification of NLs. This study investigates the use of SPECT/CT in early cycles to predict LuPSMA outcomes. Methods: Between June and December 2022, mCRPC patients who initiated the 2nd cycle of LuPSMA with SPECT/CT 24 hours post-treatment were retrospectively reviewed. We evaluated associations between TTV and the appearance of NLs at the start of the 2nd or 3rd cycle with PFS and OS using Cox regression analysis. NLs were classified as non-PSMA-avid with no or low uptake (< liver) with corresponding findings on CT and PSMA-avid (uptake > liver). All analyses were adjusted for change in PSA relative to baseline. Results: Sixty-six mCRPC patients (median age, 73.5) received a median of 4 (IQR: 3-5) cycles of LuPSMA. Median follow-up starting at 2nd cycle was 26 weeks (IQR: 21-36) with 47/66 (71%) alive at the time of the analysis. A reduction of ≥50% in PSA (PSA50) was noted in 33/66 (50%) patients. Changes in PSA and TTV at 2nd and 3rd cycle were apparently concordant in 50/66 (76%) and 42/51 (82%) and were significantly correlated (r= 0.55 and 0.56, both p<0.001). Patients with higher absolute TTV adjusted for PSA change at 2nd cycle had worse PFS and OS (HR=1.3 and 2.26) with consistent results at 3rd cycle (Table). NLs were detected in 13/66 (7/13 PSMA-avid, 6/13 non-PSMA-avid) and 7/51 patients (5/7 PSMA-avid, 2/7 non-PSMA-avid) at 2nd and 3rd cycle, respectively. Patients with NLs at 2nd cycle had higher risks of progression and death (HR=4.53 and 6.28). Conclusions: Higher SPECT/CT TTV at 2nd and 3rd cycle and detection of NLs at 2nd cycle were associated with higher risks of progression and death. Although changes in PSA and TTV were correlated, absolute SPECT/CT TTV in early cycles provided a complementary ability to predict outcomes of LuPSMA. [Table: see text]
Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.
Authors: Saliby Renee Maria , Xie Wanling , Wells J Connor , Saad Eddy , Eid Marc , Labaki Chris , Semaan Karl , Ferrier Evan , Lemelin Audreylie , Suárez Cristina , Ruiz-Morales Jose Manuel , Powles Thomas , Wood Lori , Ebrahimi Hedyeh , de Velasco Guillermo , Takemura Kosuke null , Agarwal Neeraj , Braun David A. , Heng Daniel Yick Chin , Choueiri Toni K.
Published: January 2024

400

Background: In Ph3 trials, assessment for primary endpoint of OS necessitates extended follow-up (f/u) periods, larger pool of events, and higher associated costs. We sought to determine if shorter IEs like Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients (pts) receiving ICI-based trt. Methods: We included all International mRCC Database Consortium (IMDC) pts who received contemporary approved first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last f/u. Associations of OS with TTF and TTNT status at 6-mo landmark were assessed using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by treatment (trt) and yrs of ICI start. Endpoint associations across all f/u time were evaluated using Kendall’s Tau (KT) correlation by Clayton copula. A KT >0.49 indicates a strong correlation ( Wicklin R., 2023). Results: The cohort consisted of 1667 pts with a median f/u of 15.4 mo (IQR: 7.1-28.6). Median age at 1L start was 63 yrs (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Pts who discontinued their 1L regimen within the 6-mo landmark demonstrated poor OS, with a hazard ratio (HR) of 2.74 (95% CI: 2.15-3.49). Additionally, those who transitioned to a 2L therapy within the first 6 mo showed worse OS, reflected by an HR of 2.82 (2.22-3.59). KT correlation with OS across all follow up was 0.49 (0.45, 0.52) for TTF and 0.67 (0.64, 0.69) for TTNT. Consistent results were seen across all subgroups with the strongest association in the ICI+TKI group (Table). Conclusions: TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating efficacy in ICI-based regimens.[Table: see text]
Evolving metastatic renal cell carcinoma (mRCC) treatment landscape in the post vascular endothelial growth factor (VEGF) and immune checkpoint inhibitor (IO) setting.
Authors: Shah Neil J. , Bhattacharya Rituparna , Ning Ning , Shinde Reshma , Schmier Jordana , Tan Malinda , LeMasters Traci , Sundaram Murali , Perini Rodolfo F. , Motzer Robert J.
Published: January 2024

406

Background: IO and VEGF based therapies have transformed the front-line treatment paradigm for patients with mRCC. This study's objective is to describe treatment patterns and clinical outcomes among mRCC patients in the post IO and VEGF setting. Methods: Adult patients diagnosed with mRCC between Jan 2015 - Dec 2022 and received IO and VEGF (in combination or sequence) in the first three lines of therapy after mRCC diagnosis were identified from Optum’s de-identified Clinformatics® Data Mart Database, a large retrospective claims database. Index date was defined as the date of the first (index) treatment in the post IO and VEGF setting. Patients were required to have continuous enrollment of 6 months prior to index date. Patients were categorized into 3 cohorts based on lines of index treatment (2L, 3L, 4L). Treatment patterns were described and real world (rw) time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) were estimated by Kaplan Meier analysis. Results: A total of 664 patients were included (2L:186, 3L:429, 4L:49). 37% received IO and VEGF in combination prior to index line of therapy. Median age at mRCC diagnosis was 67.0 years, with 72.7% male and 68.1% White; 11.6% died and 7.4% disenrolled during index treatment. Post IO and VEGF, cabozantinib was the most used therapy across 3 cohorts (2L: 43.5%, 3L: 35.2%, 4L: 30.6%) (Table). Median rwToT and rwTTNT for 2L, 3L, and 4L cohorts were 4.4, 5.0, and 5.6 months and 10.7, 11.7, and 9.5 months, respectively. Median OS from mRCC diagnosis was similar across the 3 cohorts (2L: 41.6, 3L: 38.7, 4L: 40.6 months); median OS from index date decreased with advancement in LOT (2L: 20.6, 3L: 14.1, 4L: 10.3 months). Conclusions: Our study is one of the largest and comprehensive study giving a unique perspective into evolving treatment patterns and outcomes for mRCC patients in the post IO and VEGF setting. Post IO+VEGF, the most common treatments were tyrosine kinase inhibitor-based treatments, and the median ToT was less than 6 months. Hence, novel treatments are needed to improve clinical outcomes for mRCC patients in the post IO and VEGF setting. [Table: see text]
Association between PET-based TheraP eligibility and 177Lu-PSMA-617 (LuPSMA) outcomes in VISION-eligible patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Demirci Ridvan Arda , Gulati Roman , Ghodsi Alireza , Nelson Peter , Cheng Heather H. , Hawley Jessica E. , Yezefski Todd , Haffner Michael C. , Montgomery Robert Bruce , Schweizer Michael Thomas , Yu Evan Y. , Chen Delphine L , Iravani Amir
Published: January 2024

41

Background: The optimal threshold based on pre-treatment PET for patient selection for LuPSMA is yet to be defined. TheraP trial applied a high threshold for PSMA-expression on PSMA PET and utilized FDG PET to exclude FDG-avid/non-PSMA-avid disease while the VISION trial used only PSMA PET with a lower threshold of PSMA-expression. The stricter criteria in TheraP trial doubled the screening failure rate compared to VISION trial, 28% vs. 12.6%. In this study among VISION-eligible patients, we aimed to compare the outcome of those who were TheraP-Eligible (TheraP-E) to TheraP-Ineligible (TheraP-I). Further, the prognostic value of FDG-PET phenotyping is investigated. Methods: This retrospective cohort study evaluated consecutive VISION-eligible mCRPC patients who received at least one cycle of LuPSMA and had both PSMA- and FDG-PET within one month of each other between June 2022 and January 2023. Patients were blindly classified as TheraP-E vs. TheraP-I. We compared whole-body semiquantitative parameters including total tumor volume (TTV), SUVmean and SUVmax and outcomes including PSA decline of ≥50% relative to baseline (PSA50), PSA-progression-free survival (PSA-PFS), and overall survival (OS) between the groups. Separately, the patients were dichotomized to having dominant FDG-avid disease (uptake > liver in most sites of disease) vs. non-FDG-avid disease and OS were compared by Cox-regression. Results: 46 patients (median age: 72, ECOG 0-2: 89%, visceral disease: 28%) were included with a median follow-up of 10 months (IQR: 8-14). 14/46 (30%) patients assessed as TheraP-I and had lower PSMA-PET SUVmean and SUVmax compared to TheraP-E patients (5.6 vs. 8.8 and 23 vs. 53, p < 0.001 for both) while other PET parameters including PSMA TTV and FDG parameters (SUVmax, SUVmean and TTV) were not statistically different. TheraP-I patients had lower PSA50 response (21% vs. 56%, p = 0.029) but PSA-PFS and OS were not significantly different compared to TheraP-E patients (Table). 37/46 (80%) patients assessed as FDG-avid had an increased risk of death compared to non-FDG-avid counterparts (Table). Conclusions: In a VISION-eligible population receiving LuPSMA, TheraP imaging-based ineligibility was associated with worse PSA response but with no significant difference in PSA-PFS or OS. Clinical investigation of the more permissive VISION inclusion criteria and the importance of FDG-avid disease using a larger sample size is warranted. [Table: see text]
Pembrolizumab plus lenvatinib (P+L) versus alternative therapies in first-line (1L) advanced renal cell carcinoma (aRCC) by IMDC risk status: A network meta-analysis (NMA).
Authors: Rane Pratik , Yan Kevin , Schmidinger Manuela , Peer Avivit , Druyts Eric , Burgents Joseph E. , Sundaram Murali
Published: January 2024

421

Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria is a widely used prognostic model in advanced RCC. Pembrolizumab plus lenvatinib (P+L) demonstrated a significant improvement in ORR, PFS, and OS versus sunitinib in subjects with cc aRCC in the KEYNOTE-581/CLEAR trial. This NMA indirectly compared the efficacy of P+L to other therapies in 1L aRCC subjects within IMDC risk groups using data from randomized clinical trials (RCTs). Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. Trials reporting results for IMDC favorable risk and/or intermediate+poor risk groups were included. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). The NMAs assuming constant hazard ratios (HRs) for OS and PFS were performed for all IMDC risk group categories. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: For the IMDC favorable risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + ipilimumab (N+I) (OR=5.35; 95% CrI: 2.59, 11.41) and nivolumab (OR=8.41; 95% CrI: 1.84, 43.77). For PFS, P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.31, 95% CrI: 0.17-0.56). For OS, no significant differences were observed compared to other alternatives in the network. For the IMDC intermediate+poor risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + cabozantinib (N+C) (OR=1.77; 95% CrI: 1.02, 3.10), N+I (OR=3.15; 95% CrI: 1.94, 5.10), and nivolumab + ipilimumab + cabozantinib (N+I+C) (OR=2.34; 95% CrI: 1.34, 4.12), pembrolizumab + axitinib (P+A) (OR=2.65; 95% CrI: 1.57, 4.44) and nivolumab (OR=4.68; 95% CrI: 1.84, 12.02). For PFS, P+L resulted in a statistically significant improvement compared to N+I (HR=0.59; 95% CrI: 0.41, 0.84) (P+A) (HR=0.64; 95% CrI: 0.44, 0.93), and avelumab + axitinib (A+A) (HR=0.65; 95% CrI: 0.46, 0.93). For OS, no significant differences were observed compared to other alternatives in the network. Conclusions: PFS analysis favored P+L over all alternative therapies in the network in favorable or intermediate+poor IMDC risk groups. ORR analysis favored P+L over all alternative therapies in the network in intermediate+poor IMDC risk groups. No significant difference in OS was observed between P+L and other alternative therapies in the network.
An observational multicenter French study on unanswered questions in patients with advanced renal cell carcinoma (aRCC) treated with cabozantinib: OCTOPUS.
Authors: Thibault Constance , Mourey Loic , Pasquier David , Bernhard Jean-Christophe , Boissier Marion , Perrot Valérie , Albiges Laurence
Published: January 2024

430

Background: Real-world studies with cabozantinib in aRCC have investigated its effectiveness and tolerability in routine practice, but questions remain unanswered including: Activity of systemic therapies after progression on Cabozantinib, patterns of long-responders and use in elderly patients. Methods: OCTOPUS study (NCT05444933) is a retrospective study of all consecutive patients (pts) treated with cabozantinib 2nd line (2L) for aRCC from March 2018 to March 2021 in 26 French centers. Pre-defined analysis included: descriptive analysis of Cabozantinib 2L regimen, activity of subsequent line (defined by treatment duration), patterns of long-term responders (defined as duration of cabozantinib more than 12 months in patients with complete, partial response or stable disease); and in elderly pts (>75 years). Results: In total, 252 patients were included. Median age was 63 years (20-86), 84.1% had clear-cell histology. At Cabozantinib 2L initiation, among 69 patients with available IMDC score, IMDC risk was favorable/intermediate/poor in 13.0 %, 49.3% and 37.7 % of the cases, respectively. Patients had an ECOG PS of 1 (45.8%) or 2 (25.8%). Bone, liver and brain metastasis (mets), were present in 130 (52.0%), 69 (27.6%) and 34 (13.6%) patients, respectively. 102 (40.5%) pts had 3 or more mets sites and 167 (66.3%) pts had a prior nephrectomy. 154 (61.1%) pts were pretreated with a tyrosine kinase inhibitor (TKi) based regimen and 94 (37.3%) were pretreated with an immunotherapy (IO) based regimen. Results are reported in the table. 157 patients received a 3rd line (3L) treatment after cabozantinib: nivolumab (55.4%) or a VEGFR TKI (26.1%) including axitinib (85.4%). In this subgroup, the median duration of treatment (DOT) and median progression free survival (PFS) were respectively 8.2 months and 8.0 months, with a disease control rate (DCR) of 80.3 % for Cabozantinib 2L. Conclusions: We reported the pattern of use of Cabozantinib in RWE, highlighting feasibility in elderly and long-term exposure in long responders as well as subsequent therapy activity. [Table: see text]
Pharmacodynamics and gene expression analysis of patients with renal cell carcinoma treated with combination nivolumab and TPST-1120 in a phase I clinical trial (NCT03829436).
Authors: Bastos Bruno R. , Standifer Nathan , Garje Rohan , Whiting Sam H.
Published: January 2024

438

Background: TPST-1120 is a first-in-class, oral inhibitor of peroxisome proliferator-activated receptor (PPAR-α), a fatty-acid ligand-activated transcriptional factor that controls the expression of multiple genes involved in fatty acid oxidation (FAO), angiogenesis and inflammation. In a phase 1 open-label trial, TPST-1120 was administered as a single agent and in combination with nivolumab in multiple tumor types. Among the tumor types treated, 4 patients in the combination arm had Renal Cell Carcinoma (RCC). 2 of the patients experienced clinical and radiographic response confirmed by RECIST. On this study, we plan to further study the pharmacodynamic and radiographic changes in these patients with RCC to further understand signals to identify patients who may benefit from this treatment. Methods: Mutational analysis of ctDNA was assessed using the PredicineCARE assay (Predicine Inc.), and lipid analysis was performed by tandem mass spectrometry. Gene Expression changes were quantified using the nCounter PanCancer Iune Profiling Panel (Nanostring Inc.) supplemented with 30 PPAR-α target genes. The radiographic Analysis was performed with CT chest-abdomen-pelvis and response evaluated using RECIST criteria. Results: RCC patients with PR (2/4) confirmed by RECIST exhibit greater reductions in 6 PPAR-α regulated genes. They had an early increase in thrombospondin (TSP-1) level due to PPAR-α inhibition. An increase in long-chain fatty chain fatty acids was seen including circulating FFA, lysophosphorylcholine (LPC) or lysophosphorylethanolaine (LPE). They also had great reductions in 6 PPAR-α regulated genes including ACAD8, ACSL3, CPT2, FABP1, FABP3, HADHB. Conclusions: There is a paucity of treatment options for patients with stage IV RCC post anti-PD1 and anti-VEGF therapies. Novel therapies on this clinical scenario are needed. On this abstract we showed radiographic and pharmacodynamic data on patients with RCC who achieved a clinical partial response by RECIST on the phase I clinical trial TPST1120-001. The trial explored the se of a PPAR-α inhibitor in combination with Nivolumab. The pharmacodynamic data indicates that there is fatty acid oxidation perturbation and immune gene expression changes as potential biomarkers of clinical benefit. PI3K pathway or IDH mutations may indicating a signal that RCC patients may benefit from this combination therapy. Larger studies in the future may be designed to further explore the use of this combination in patients with RCC. Clinical trial information: NCT03829436 .
Low- and high-volume disease in mHSPC, from CHAARTED to PSMA-PET: An international multicenter retrospective study.
Authors: Unterrainer Lena , Hope Thomas A. , Fendler Wolfgang P. , Ndlovu Honest , Barbato Francesco , Sathekge Mike , Herrmann Ken , Czernin Johannes , Calais Jeremie
Published: January 2024

44

Background: High-volume disease (HVD) and low-volume disease (LVD) definitions are based on conventional imaging (CI = CT + bone scan (BS)) according to CHAARTED. Volume of disease is associated with overall survival and used for treatment decisions in mHSPC patients. It remains unknown how these definitions transfer to PSMA-PET. Methods: mHSPC patients from 4 international sites who underwent PSMA-PET+BS within a maximum time interval of 100 days and without any new treatment in between were retrospectively included. CHAARTED stratification into HVD/LVD was applied to BS, CT, MRI and PSMA-PET. HVD was defined by the presence of visceral metastases and/or ≥ 4 bone metastases (with ≥ 1 beyond spine / pelvis). EXINIbone 3.4 (EXINI Diagnostics) was used for the automated bone scan index (aBSI) and the number/localization of lesions on BS. The whole-body (WB) PSMA-PET positive tumor volume (PSMA-TV) was obtained using a semi-automatic thresholding method on Affinity 3.0.2 (Hermes Medical Solutions). Results: Fifty-sevenpairs of PSMA-PET/CT+BS were included (median PSA 226.0 (0.2–2840.0 ng/ml). Based on CI, 16/57 patients had CI-HVD (28.1%) and 41/57 CI-LVD (71.9%). Based on PSMA-PET, 25/57 patients had PSMA-HVD (43.9%) and 19/57 PSMA-LVD (33.3%), 13/57 (22.8%) patients had on PSMA-PET no PSMA-positive or only local / N1-disease. Upshift and downshift from CI to PSMA-PET occurred in 22/57 (38.6%): 9/57 (22.0%) patients were upstaged and 13/57 (22.8%) were downstaged by PSMA-PET. The downshifted patients had no PSMA-PET-positive lesion or only in the prostate fossa while CI was M1 disease. The mean WB-PSMA-TV and aBSI were for CI-HVD was 778.2 ml (0.3–3734.0) and 3.8% (0–11.7), for CI-LVD 51.6 ml (0–228.0) and 0.1% (0–0.6), for PSMA-HVD 573.7 ml (7.9–3734.0) and 2.6% (0–11.7) and for PSMA-LVD, 49.4 ml (1.6–228.0) and 0.1% (0–0.6), respectively. Conclusions: Stage migration between LVD and HVD from CI to PSMA-PET occurs both by up- and downstaging. HVD/LVD based on PSMA PET/CT should be redefined based on patients’ outcome.
High expression of sialylated cancer-derived IgG and survival in metastatic clear cell renal cell carcinoma.
Authors: Wu Jie , Cui Hong-Lei , Shi Hongzhe , Zhou Ai-Ping , Shou Jianzhong
Published: January 2024

443

Background: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has evolved from cytokine regimens to targeted therapy, and now immunotherapy-based drug combinations over the past two decades. However, there is a lack of confirmed prognosis biomarkers for mccRCC patients. The International mRCC Database Consortium (IMDC) risk model is the most widely used effective biomarker for prognostication in mccRCC. Immunoglobulin G (IgG), well known as immune molecule secreted by B cells, has recently been detected in various types of cancer cells, named as cancer-derived IgG. Notably, it has been demonstrated that IgG derived from epithelial cancer cells displays unique N-glycosylation, which is highly sialylated (SIgG). In this study, we aimed to explore the expression of SIgG in mccRCC tissues using the monoclonal antibody RP215, and evaluated the correlation of SIgG expression level with clinicopathological factors and prognosis of mccRCC patients. Methods: A total of 179 mccRCC patients with complete clinicopathological information and survival data were enrolled. Tumor tissues were collected during surgery and fixed in 10% buffered formalin, embedded in paraffin. Tissue microarray slides were then constructed for immunohistochemistry (IHC). The primary end point was overall survival (OS), defined as the time from initiation of systemic treatment to death from any cause or last follow-up. Results: The results of IHC showed that SIgG was mainly expressed in the cell membrane and cytoplasm, and the high expression of SIgG was significant correlated with poor OS in mccRCC patients (HR = 2.281, P < 0.001). Moreover, based on multivariate Cox regression analysis, high SIgG expression was identified as an independent prognostic variable for OS in mccRCC patients (HR = 2.110, P < 0.001), as well as poor IMDC risk group (HR = 2.123, P = 0.018). The time-dependent ROC curve also suggested the promising prognostic value of SIgG expression, with a 5-year AUC of 0.679 for SIgG alone and 0.742 for SIgG combined with IMDC risk model. In addition, subgroup analyses were performed to further assess prognostic value of SIgG for mccRCC patients among groups based on IMDC risk group, metastatic site, and metastatic time. The prognostic value of SIgG was more marked in patients with intermediate (HR = 2.191, P = 0.019) and poor (HR = 2.111, P = 0.058) IMDC risk group, and lung metastasis (HR =1.970, P = 0.009). Notably, the prognostic value of SIgG was significant in both synchronous and metachronous metastasis patients. Conclusions: SIgG appears to be a reliable predictor for the outcome of mccRCC patients, and SIgG combined with IMDC risk model was a more effective prognostic model than IMDC risk group alone.
Peripheral blood cell counts as biomarkers of clinical benefit in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) receiving immune checkpoint inhibitor (ICI) combination (combo) therapies.
Authors: Feinaj Ardit , Nathani Kaizen , Touma Amina , Elias Roy , Pallauf Maximilian , Markowski Mark Christopher , Carducci Michael Anthony , Singla Nirmish , Ged Yasser
Published: January 2024

446

Background: Numerous combos of ICIs and Tyrosine Kinase Inhibitors (TKIs) have received approval for the management of mccRCC. Specific peripheral blood cell counts reflect inflammation and impact anti-tumor immunity, and here we investigated their role as biomarkers of clinical benefit to ICI combos in RCC. Methods: We performed a retrospective study of 179 mccRCC patients treated with ICI combos ≥ 4 weeks (2013-2023), where we examined baseline and 6-week post-treatment Neutrophil to Lymphocyte ratio (NLR), Red cell Distribution Width (RDW), and eosinophil values. We categorized these values as High (H) or Low (L) based on baseline medians. Our analysis included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to next treatment (TNT). Kaplan-Meier methods and the log-rank test were used to evaluate time from start of ICI combos to the event of interest. Results: Our analysis included 111 eligible ICI-naïve mccRCC patients median age 63, 76% male. IMDC risk scores categorized 22% as favorable, 53% intermediate, and 25% poor risk. Treatment included 50 (45%) patients on ICI+ICI combos with a median therapy duration of 6.3 months, and 61 (55%) on ICI+TKI with a median duration of 8.8 months. In the ICI+ICI group, median OS was 28.2 months (95% CI 20.7-38.4), PFS 5.5 months (95% CI 3.7-7.8), and TNT 12.7 months (95% CI 7.4-20.4). In the ICI+TKI group, median OS was 21.7 months (95% CI 17.1-25.4), PFS 7.4 months (95% CI 5.6-11.1), and TNT 12.5 months (95% CI 9.7-16.4). The ORR was 38% in the ICI+ICI group, and 56% in the ICI+TKI group (p=0.062). No differences were seen with NLR. In the ICI+ICI group, higher baseline RDW levels were correlated with a shorter TNT, while higher eosinophil levels at week 6 were correlated with longer PFS and TNT (significant results highlighted in the table below). Conclusions: Eosinophil levels and RDW are potentially readily available biomarkers in the clinic for predicting and monitoring ICI combo treatment outcomes in mccRCC patients. Validation of these results in larger cohorts is warranted. [Table: see text]
Tumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial.
Authors: El Ahmar Nourhan , Matar Sayed , Jegede Opeyemi , Nabil Laimon Yasmin , Savla Varunika , Bagheri Sheshdeh Aseman , Denize Thomas , Mohanna Razan Assaad , Choueiri Toni K. , Catalano Paul J. , Braun David A. , Haas Naomi B. , Hammers Hans J. , Bilen Mehmet Asim , Stein Mark N. , Sosman Jeffrey A. , Wu Catherine J. , McDermott David F. , Atkins Michael B. , Signoretti Sabina
Published: January 2024

448

Background: There is evidence that intratumoral myeloid cell infiltration can modulate response to immune checkpoint inhibitors in some tumor types, but its role in ccRCC remains unclear. Here, we investigated the role of tumor-infiltrating CD163-positive macrophages as a determinant of clinical outcome to anti-PD-1 therapy in patients (pts) with advanced ccRCC treated with first-line nivolumab therapy as part of the HCRN GU16-260 clinical trial. Methods: Primary tumor tissues from pts with ccRCC (n= 67) were analyzed by multiparametric immunofluorescence (IF). Image analysis algorithms were used to assess the density of CD163-positive cells (dCD163) in tumor areas with high CD8+ T cell-infiltrates. In addition, dCD163 was also assessed in randomly selected tumor areas. Log-transformed densities were correlated with objective response rate (ORR) and progression-free survival (PFS) using Cox proportional hazards and binary logistic (modeling odds of attaining objective response) regression analysis, respectively. Alpha level was set a priori at 5% (2-sided). The functional form of CD163 for the PFS endpoint was obtained using a smoothed martingale residual plot. Results: Analysis of dCD163, assessed in high-CD8+ cell tumor areas and measured as a continuous variable, showed a positive association with ORR (OR= 2.21, p= 0.002) and PFS (HR= 0.77, p= 0.028). However, visual inspection of the dCD163 functional form plot for PFS revealed a threshold effect at the raw (log-transformed) value of 262.5 (5.6) cell/mm2. Similar to the entire cohort, in patients with dCD163 below this threshold (n= 54), dCD163 was positively associated with PFS (HR= 0.61, p<.001). In contrast, in patients with dCD163 above this threshold (n=13), results suggested the presence of a negative association between dCD163 and PFS (HR= 1.36, p= 0.726). Of note, similar findings were obtained by analyzing dCD163 assessed in random tumor areas. Conclusions: Levels of tumor-infiltrating CD163-positive macrophages are associated with improved clinical outcomes to first-line nivolumab in pts with advanced ccRCC up to a density threshold, above which an association with poor outcomes is noted. Further investigations into the role of tumor-infiltrating myeloid cells in predicting outcomes to anti-PD-1-based therapies are ongoing. Clinical trial information: NCT05403541 .
Prognostic value of circulating tumor DNA fraction (TF) for patients with metastatic renal cell carcinoma (mRCC).
Authors: Zurita Amado J. , Danziger Natalie , Scott Takara , Gjoerup Ole , Zhong Lei , Tukachinsky Hanna , Ross Jeffrey S. , Graf Ryon
Published: January 2024

455

Background: Risk stratification, based on the IMDC classification, is central to treatment decisions for patients with mRCC. The strongest prognostic feature in the original validation was the clinical assessment of patient frailty through performance status (PS). Although inexpensive and ubiquitous, clinical features such as PS are prone to degrees of subjectivity and considerable variation in assessment from practitioner to practitioner. Recent work (Reichert et al. 2022, Annals of Oncology) observed that TF levels around the initiation of new treatment were prognostic independently of standard clinical features including ECOG PS, in advanced/metastatic lung, breast, prostate, and colorectal cancers, but has not yet been investigated in mRCC. Methods: This study used a cohort of patients in the de-identified nationwide, U.S. based Flatiron Health-Foundation Medicine renal cell clinico-genomic database, which originated from approximately 280 US cancer clinics (~800 sites of care), who underwent genomic testing as part of routine care. TF estimation on FoundationOne Liquid CDx was based on a composite algorithm incorporating multiple factors including aneuploidy and variant allele frequency of canonical alterations. Clinical characteristics, laboratory and treatment data were captured from the electronic health record. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by TF level. Results: 45 patients with mRCC and liquid biopsy testing had TF assessments within 90 days of start of new treatment. Patients with TF≥1% (15 of 45) had younger median age (58y vs. 66y, p = 0.041) and higher prevalence of calcium levels above upper limit of normal (46% vs. 4%, p < 0.001). Higher TF (≥1%) was associated with less favorable rwPFS (hazard ratio (HR) 1.41, 0.70-2.82, p=0.34) and rwOS (HR 2.54, 1.08-5.96, p=0.033). In the 15 patients with TF ≥1%, we observed detection of known pathogenic genomic alterations in VHL (7/15, 47%), SETD2 (4/15, 27%), PBRM1 (4/15, 27%), BAP1 (3/15, 20%). Conclusions: In this initial cohort study, ctDNA TF shows prognostic significance in mRCC with potential to inform expected longevity of patients. Liquid biopsy detects alterations characteristic of mRCC genomics, supporting its utility to identify drivers and potential targetable alterations. Risk stratification based entirely upon algorithmic determination independent of human interpretation has the potential to improve risk stratification in mRCC and improve treatment decisions. Expansion of our cohort and survival data maturation will allow for evaluation of whether TF may be a useful addition to the established IMDC clinical classification and improve risk stratification and treatment assignment.
A convolutional neural network model using intraprostatic patterns of [F18]DCFPyL uptake in PSMA PET images to predict synchronous metastases.
Authors: Juarez Jesus Eduardo , Benitez Cecil Mayra , Rzechowski Kamil , Sjöstrand Karl , Anand Aseem , Sonni Ida , Berenji Gholam Reza , Duriseti Sai , Rettig Matthew , Nickols Nicholas George
Published: January 2024

46

Background: [F18]DCFPyL (PyL) is a PSMA targeted imaging agent that provides whole-body staging of prostate cancer. Image analysis of the primary tumor using deep learning algorithms might offer additional insight into disease biology, including co-existing metastatic disease. We developed convolutional neural network (CNN) models using inputs from the entire prostate on PyL images along with auto-segmented hot spots within the of primary prostate cancer tumor to predict synchronous metastases and compared the models against established models built from clinico-pathologic data. Methods: 91 Veterans with de novo prostate cancer were imaged with PyL PSMA PET/CT for initial staging (46% with metastatic disease). The PyL images of the prostate were analyzed using aPROMISE, which autosegments, localizes, and quantifies disease on PSMA PET. The segmentations of the prostate were used to map the PyL PET image of the prostate. Both the entire prostate, as well as aPROMISE defined hot spots were used as inputs for the CNN, where, according to attention map analysis, the hotspot information helps the network understand the location and extent of tumors. The CNN model architecture was based on SqueezeNet v2. The dataset was split into training, validation and test sets using stratified random sampling. The area under ROC curve (AUC) was computed to determine the performance of the model in predicting the presence of metastases and the test predictions were compared with ground truth (M1). Training was repeated 50 times and the best performing experiment was identified. Prediction scores from UCSF-CAPRA and UCLA PSMA risk calculator were used as comparators. Results: The best CNN model had an AUC of 0.89 for prediction of metastatic disease (median 0.72, ICR 0.64 and 0.8). For comparison, the AUC from the UCSF-CAPRA score and UCLA-PSMA risk calculator (any upstaging on PET), which rely on clinicopathologic information, had AUCs of 0.729 and 0.754 in this dataset, respectively. Conclusions: The CNN based model using PyL imaging demonstrates that synchronous metastases can be predicted from intraprostatic PyL uptake patterns alone with a predictive accuracy in this dataset that is at least comparable to published prediction models based on clinicopathologic features. This study raises the hypothesis that PyL CNN-based models could be developed to prognosticate metastatic progression.
PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.
Authors: Cancel Mathilde , Naffrichoux Jérémie , Poupin Pierre , Pouillot William , Linassier Claude , Rioux-Leclercq Nathalie , De Vries-Brilland Manon , Mourey Loic , Laguerre Brigitte , Oudard Stephane , Gross-Goupil Marine , Gravis Gwenaelle , Rolland Frederic , Moise Laura , Emambux Sheik Muhummud Fardeen , Vassal Cecile , Zanetta Sylvie , Penel Nicolas , Albiges Laurence , Fromont Gaelle
Published: January 2024

463

Background: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its associations with angiogenesis pathways expressions, to search for potential therapeutic targets. Methods: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 75 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to evaluate the prognostic impact on overall survival (OS) of PD-L1 expression in metastatic pRCC. Secondary endpoints were to describe the expression of the other immune markers and of angiogenic pathways and to estimate the associations between the expression of PD-L1 and the expressions of the other markers or angiogenic pathways. Results: In median, patients were 61 years old at metastatic diagnosis. Concerning their first-line metastatic treatment, 67 (89%) had received Sunitinib, and 8 (11%) had received Everolimus. The Karnofsky Performance Score at treatment initiation was ≥ 80 for 62 (83%) patients. Overall, 25.3% of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.3%), PD-1 and LAG-3 were positive in 17.3% both. Concerning the angiogenic markers, CAIX was expressed in 46.7% of tumors, c-MET in 41.3%. None of these markers were significantly associated with PD-L1 expression. 64% (48/75) expressed at least one immune marker, and 40% (30/75) were “double-positive”, as they expressed both immune and angiogenic markers. In univariate analysis, OS was significantly shorter for patients with PD-L1 positive pRCC (HR=3.3; 95%CI=1.3-8.6; p=0.01). A multivariate analysis confirmed a significant association between PD-L1 expression and shorter survival (HR=5.4; 95%CI=1.4-20.9; p=0.01). Conclusions: These results reinforce clinical data on the expected benefit of immunotherapy in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in our multicenter cohort.