bluuebunny/crossref_metadata_2025 huggingface dataset:
Penile cancer: 20 years of experience in a reference oncology center in Mexico.
Authors: Rodriguez Rosales Yuridia Evangelina , Guerra Cepeda Abraham , Najera Rubi Janday , Rivera Valdés Francisco Daniel , Hernandez Barajas David , Vidal-Gutiérrez Oscar , Zayas-Villanueva Omar Alejandro
Published: March 2023

6

Background: Penile cancer is a rare neoplasm (<1%), being more common in underdeveloped countries, 10-20% of male neoplasms, with a mean age at diagnosis of 60 years. The number of annual cases in Mexico is only 660 cases, 0.35% of all neoplasms. Its initial symptomatology as a palpable or ulcerated lesion must be differentiated from infectious processes. From 30 to 60% of cases debut with inguinal lymphadenopathies and distant metastases in 1 to 10%. Methods: Cross-sectional, retrospective cohort study of patients diagnosed with penile cancer, who received medical care at the medical oncology service of the University Cancer Center from January 1, 1999 to December 31, 2019. Results: Of the 103 patients analyzed in this study, the mean age was 55 years (27-91 years), the highest level of schooling obtained was primary in 18.5%, being mostly from the state of Nuevo León in 61.1%. of the cases. The duration of symptoms was 17 months on average, and the time interval between diagnosis and receiving medical or surgical treatment was 97 days. Regarding the pathological characteristics of penile cancer, the average tumor size was 41.4mm, the most frequent histological type was squamous in 91.3%. Regarding the classification by clinical stages, patients in clinical stage I was 8%, II 10.6%, III 26.2% and IV 32%, not being recorded accurately in 23.3% of cases. The initial medical treatment was surgical in 81.5% of the cases, with partial phallectomy being the procedure of choice in 57.2% of the patients, with the presence of positive margins in 9.5% of the patients. Lymph node involvement was 71.2% of the cases and lymph node dissection was only performed in 31% of the patients. Those who received chemotherapy were 27.1% of the patients, the majority, 57.1% in the adjuvant setting, the most commonly used scheme was cisplatin with 5-fluoroacyl in 60.7%. Radiotherapy was used in 25.2% of the patients, being the adjuvant modality in 65.4% and in the palliative context in 34.6%, with an average dose of 46.5 Gy and 8 fractions. Conclusions: A diagnosis at an earlier age was observed in our court, being 55 years old vs 60 years old reported in the literature. A delay in diagnosis of up to 12 months has been reported in 15-50% in the literature, being higher in our population with a mean of 17.7 months. Poor adherence to treatment and clinical follow-up was observed, since one in 4 patients only goes to oncology once and loses follow-up. Penile cancer is a rare, psychologically devastating neoplasm with delayed diagnosis, advanced clinical disease, decreased survival, and high recurrence rates despite bimodal or trimodal treatment. A multidisciplinary team approach should be sought to achieve better oncological results and timely detection of cancer in earlier stages.
Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial.
Authors: Burotto Mauricio , Powles Thomas , Escudier Bernard , Apolo Andrea B. , Bourlon Maria Teresa , Shah Amishi Yogesh , Suárez Cristina , Porta Camillo , Barrios Carlos H. , Richardet Martin , Gurney Howard , Kessler Elizabeth R , Tomita Yoshihiko , Bedke Jens , George Saby , Scheffold Christian , Wang Peter , Fedorov Viktor , Motzer Robert J. , Choueiri Toni K.
Published: March 2023

603

Background: First-line nivolumab plus cabozantinib (N+C) demonstrated superiority over sunitinib (S) with 25.4 mo minimum follow-up (median, 32.9 mo) in patients (pts) with aRCC in the CheckMate 9ER trial. Here, we report survival, response per blinded independent central review (BICR), and safety after 3 y minimum follow-up in all randomized pts and by IMDC risk score. Methods: Pts were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, region) to N 240 mg flat dose IV Q2W + C 40 mg PO QD vs SUN 50 mg PO for 4 wk (6-wk cycles) until disease progression or unacceptable toxicity (max N treatment, 2 y). Primary endpoint: progression-free survival (PFS) by BICR. Secondary endpoints: overall survival (OS), objective response rate (ORR) by BICR, and safety. Results: In total, 323 pts were randomized to N+C and 328 to S. With 36.5 mo minimum follow-up (median, 44.0 mo), PFS and OS benefits were maintained with N+C vs S in intent-to-treat pts. Median PFS was 16.6 vs 8.4 mo (HR 0.59 [95% CI 0.49–0.71], P < 0.0001) and median OS was 49.5 vs 35.5 mo (HR 0.70 [95% CI 0.56–0.87], P = 0.0014). ORR (95% CI) was higher with N+C vs S (56% [50–62] vs 28% [23–33]), and 13% vs 5% of pts achieved complete response (CR), respectively. Median duration of response was 22.1 vs 16.1 mo for N+C vs S. PFS, OS, and response are reported across prespecified IMDC risk groups in the table. Any-grade treatment-related adverse events (TRAEs) occurred in 97% vs 93% of pts treated with N+C vs S (grade ≥ 3 TRAE, 67% vs 55%). TRAEs led to discontinuation of C only in 10% of pts, N only in 10% of pts, N+C in 7% of pts, N or C in 28% of pts, and S in 11% of pts. Conclusions: After 3 y minimum follow-up, survival and response benefits were maintained with N+C and remained consistent with previous follow-ups. Median OS with N+C improved by 11.8 mo since the previous data cut. Responses with N+C were durable, with higher CR rates with N+C vs S regardless of IMDC risk group. No new safety signals emerged with additional follow-up in either arm. These results continue to support N+C as a first-line treatment for pts with aRCC. Clinical trial information: NCT03141177 . [Table: see text]
Outcomes by IMDC risk in the COSMIC-313 phase 3 trial evaluating cabozantinib (C) plus nivolumab (N) and ipilimumab (I) in first-line advanced RCC (aRCC) of IMDC intermediate or poor risk.
Authors: Powles Thomas , Motzer Robert J. , Albiges Laurence , Suárez Cristina , Schutz Fabio A. B. , Heng Daniel Yick Chin , Chevreau Christine , Kanesvaran Ravindran , Gurney Howard , Wang Fong , Mataveli Fabio , Chang Yu-Lin , van Kooten Losio Maximiliano , Choueiri Toni K.
Published: March 2023

605

Background: In COSMIC-313 (NCT03937219), C+N+I significantly improved progression-free survival (PFS) compared with N+I in first-line aRCC of IMDC intermediate or poor risk (Choueiri ESMO 2022). Here, outcomes are analyzed by IMDC risk group. Methods: A total of 855 patients (pts) with clear cell aRCC of IMDC intermediate or poor risk were randomized to receive C 40 mg QD or matched placebo (P), stratified by region and IMDC risk. Both treatment groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles followed by N (480 mg IV Q4W); N was administered for up to 2 years. The primary endpoint was PFS by blinded independent radiology review (BIRC) per RECIST 1.1 in the first 550 randomized pts (PITT population). The secondary endpoint was overall survival (OS) in all randomized pts; objective response rate (ORR) and safety were additional endpoints. Results: Overall, 75% of pts were IMDC intermediate and 25% were poor risk. Meaningful differences in baseline characteristics for intermediate vs poor risk in the PITT population were observed for KPS ≥90 (67% vs 47%), prior nephrectomy (71% vs 44%), and ≥2 target/non-target lesions per BIRC (68% vs 83%); characteristics were balanced across treatment arms for intermediate risk but some imbalances were seen for poor risk (42% for C+N+I vs 52% for P+N+I had KPS ≥90 and 37% vs 50% had prior nephrectomy). In intermediate risk pts, PFS was improved with C+N+I (HR 0.63, 95% CI 0.47–0.85), and ORR and DCR (PITT population) were numerically higher (Table). For poor risk pts, no difference in PFS and ORR was apparent, but DCR was numerically higher with C+N+I. PD as best response was lower with C+N+I vs P+N+I in both risk groups. Duration of response was not reached (NR) in each treatment group. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 74% with C+N+I vs 42% with P+N+I for intermediate risk and 67% vs 38% for poor risk. TRAEs led to discontinuation of all treatment components in 14% vs 5% for intermediate risk and 5% vs 4% for poor risk. Additional analyses relevant to IMDC risk group will be presented. Conclusions: In COSMIC-313, C+N+I improved PFS vs P+N+I in first-line aRCC of IMDC intermediate or poor risk; subgroup analysis suggested that the benefit was primarily in intermediate risk pts. Follow-up for OS is ongoing. Clinical trial information: NCT03937219 . [Table: see text]
CaboPoint: Interim results from a phase 2 study of cabozantinib after checkpoint inhibitor (CPI) therapy in patients with advanced renal cell carcinoma (RCC).
Authors: Albiges Laurence , Powles Thomas , Sharma Anand , Venugopal Balaji , Bedke Jens , Dutailly Pascale , Qvick Bryan , Martin-Couce Lidia , Perrot Valérie , Grünwald Viktor
Published: March 2023

606

Background: First line CPI-based therapy is the standard of care for advanced RCC. There is a lack of prospective data for cabozantinib after 1L CPI regimens, which is addressed in this study. Methods: CaboPoint (ClinicalTrials.gov identifier: NCT03945773) is an ongoing Phase 2, multicenter, open-label study of cabozantinib in adults with unresectable, locally advanced, or metastatic clear cell RCC who have progressed after 1L CPI-based therapy. Prior treatment with cabozantinib was not permitted. Patients received cabozantinib in two independent cohorts (cohort A [post nivolumab + ipilimumab] and cohort B [post CPI + vascular endothelial growth factor targeted therapy]). Both cohorts received cabozantinib (60 mg/day as starting dose) until study end (18 months after last patient’s enrollment). The primary endpoint was objective response rate (ORR) in Cohort A per RECIST 1.1 evaluated by independent central review; ORR by investigator review has been included as a secondary endpoint for both cohorts. Here we report results from the pre-planned interim analysis of ORR based on investigator assessment in both cohorts that occurred when 80% of patients in cohort A reached at least 3 months of treatment. Results: At the time of this interim analysis, 88 patients had 3 months of follow up (60 in cohort A and 28 in cohort B). Baseline characteristics were similar across cohorts. Patients had an Eastern Cooperative Oncology Group status of 0 (55.0% / 60.7%) and an intermediate or poor International Metastatic RCC Database Consortium risk (46.3% and 13.0% / 40.7% and 11.1%). The most common prior treatment in cohort B was pembrolizumab + axitinib (71.4%), followed by avelumab + axitinib (28.6%). ORR and best overall response at three months of follow-up as assessed by the Investigator are shown in the table. Conclusions: In this interim analysis, cabozantinib demonstrated preliminary efficacy in patients with advanced RCC after progression on CPI-based combination therapy, irrespective of 1L regimen. The CaboPoint trial is ongoing, with the final analysis anticipated in September 2023. Clinical trial information: NCT03945773 . [Table: see text]
Implications of ethnicity among patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab (nivo/ipi).
Authors: Leong Sally , Ali Sana , Zengin Zeynep Busra , Meza Luis A , Dizman Nazli , Ebrahimi Hedyeh , Govindarajan Ameish , Castro Daniela V. , Li Xiaochen , Kim Tane , Melamed Sam , Onyshchenko Mykola , Pal Sumanta Monty , Chehrazi-Raffle Alex
Published: March 2023

613

Background: Existing literature has reported differences in clinical outcomes by ethnicity in patients receiving immune checkpoint inhibitors (Olsen et al Front Oncol 2021). We investigated real-world outcomes between Latinx and non-Latinx mRCC patients treated with first-line nivo/ipi within a safety-net healthcare system and at a tertiary care center in Southern California. Methods: We performed a retrospective analysis of mRCC patients who received nivo/ipi within the Los Angeles County Department of Health Services (DHS), a safety-net healthcare system, and the City of Hope Comprehensive Cancer Center (COH), a tertiary oncology center, between Jan. 1, 2015 and Dec. 31, 2021. Patients were identified using institutional databases and clinical data were compiled from electronic health records. Patients with pathologic diagnosis of mRCC, age > 18 years and receipt of nivo/ipi as first-line therapy were included. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model with adjustments for other covariates. Results: Of 94 patients, 66 (70%) were male, 90 (94%) had clear-cell histology, and 87 (93%) had IMDC intermediate/poor risk disease. Forty patients (43%) were Latinx. Fifty (53%) and 44 (47%) patients received their care at a tertiary care center and within a safety-net healthcare system, respectively. Most Latinx patients (95%) were treated at DHS, and most non-Latinx patients (89%) were treated at COH. Latinx patients were significantly older than non-Latinx patients (59.5 vs 55 years, p=0.008). IMDC risk classification, body mass index, history of nephrectomy, and number of comorbidities were similar between both groups. Pooled analysis by ethnicity demonstrated significantly shorter PFS in Latinx versus non-Latinx patients (10.1 vs 25.2 months, HR 3.61, 95% CI 1.96-6.66, p= <0.01). Adjusting for age, gender, IMDC risk classification, history of nephrectomy, and number of co-morbidities, multivariate analysis revealed a HR of 3.41 (95% CI 1.31-8.84; p=0.01). At a median follow up of 11.0 months, the median OS was not met in either arm at the time of data cutoff (NR vs. NR, HR 1.34, 95% CI 0.44-4.11). Conclusions: Compared to non-Latinx patients,Latinx patients demonstrated shorter PFS; no difference was observed in OS although these data were immature. As the majority of Latinx patients received their care at DHS, our data suggest that disparities in access to care may significantly contribute to differences in clinical outcomes of mRCC patients receiving nivo/ipi.
Association of primary tumor radiomic phenotypes and outcomes in patients (pts) with metastatic renal cell clear cell carcinoma (mRCC) treated with cytoreductive nephrectomy (CN).
Authors: Cunha Mateus Trinconi , Stangler Lucas , Freire Pedro , Pinto Paulo Victor Alves , Coelho Fernando Morbeck Almeida , Viana Públio , Cordeiro Mauricio , Nahas William Carlos , Mota Jose Mauricio
Published: March 2023

622

Background: Despite the advances in systemic therapy for mRCC, CN may benefit a subset of pts. We investigated the correlation of clinical outcomes with primary tumor radiomics and radiology measurements of primary and metastatic lesions in mRCC pts treated with CN. Methods: We searched our institutional database for mRCC pts referred for CN from July 2011 to October 2019. Key eligibility criteria included clear cell histology, measurable metastatic disease, and OS >60 days from CN, to avoid surgery-related deaths. Demographics and IMDC risk strata were collected from medical charts. Volumetry and radiomic features (first and second order) were assessed in the arterial phase abdominal computerized tomography (CT) of the primary lesion. Metastatic disease foci were segmented from venous phase CT and measured. Bone disease and <1cm visceral metastases were disregarded for 3-axial measurement. After dimensionality reduction of the radiomic features with Uniform Manifold Approximation and Projection, an unsupervised Gaussian Mixture Model (GMM) clustering was performed. Characteristics of different clusters were compared with Mann-Whitney U test and univariate Cox regression estimated the effect on outcomes. Results: From 54 mRCC pts treated with CN, 39 were included. Median age was 60 years-old. Most patients were male (74%) and intermediate-risk by IMDC (64%). Sites of metastasis included lung (44%), bone (38%), and adrenal (21%). GMM identified 4 distinct clusters from radiomic features, which were grouped according to median OS relative to all pts (2.8 years): Group A (below mOS) and Group B (above mOS). The table shows the association of different factors with OS. Group B had longer median OS (3.4 vs. 1.8 years, p=0.009), progression-free survival (16.8 vs. 9.8 months, p=0.024), systemic treatment-free survival (9.5 vs. 3.8 months, p=0.028), and survival during first-line tyrosine kinase inhibitor (2.2 vs. 0.9 years, p=0.016). Group men had a lower primary-to-whole-body burden ratio compared to Group A (median 0.83 vs. 0.99, p<0.01). Only IMDC risk criteria (HR 1.97, p<0.01) and radiomic group B (HR 0.35, p=0.01) correlated with OS in univariate Cox analysis. Conclusions: Our study suggests that radiomics of the primary lesion may predict OS in mRCC pts after CN, despite limited by its retrospective nature and small sample size. Further validation in larger datasets is warranted. Univariate Cox proportional hazards of prognostic factors on OS. [Table: see text]
Patient and physician preferences for adjuvant treatment of renal cell carcinoma: A discrete-choice experiment.
Authors: Calhoun Shawna R , Vass Caroline , Myers Kelley , Imai Kentaro , Bussberg Cooper , Bhattacharya Rituparna , Pinto Cathy Anne , Poulos Christine
Published: March 2023

635

Background: Although a handful of studies have elicited treatment preferences in renal cell carcinoma (RCC), most focused on advanced disease. This study elicited United States patients’ and physicians’ preferences for adjuvant treatment characteristics. Methods: Patients with physician-confirmed RCC and (physician-defined) intermediate high or high risk of recurrence and physicians who treat such patients completed online surveys in Q1-Q2 2022 with a discrete-choice experiment. Hypothetical treatments were described by median disease-free survival (DFS); 5-year overall survival (OS) rate; mode and frequency of administration; need for concomitant daily pill; treatment duration; and the risks of severe diarrhea, fatigue, and dizziness. Preference weight estimates from random parameter logit analysis were used to calculate the conditional relative importance of attributes and risk tolerance measures. Results: 250 patients (50% post-nephrectomy) and 250 physicians (64% oncologists; 36% urologists) completed the survey. OS was the most important attribute to both patients and physicians, but DFS was also important (Table). OS had a greater influence on physicians’ choices than on patients’ choices. On average, OS was 3.2 and 2.5 times as important as DFS and 5.8-9.1 and 2.4-3 times more important than the evaluated risks for physicians and patients, respectively. Further, DFS was 1.8-2.9 times more important to physicians than the evaluated risks, while the importance of DFS and risks were nearly equivalent for patients. The need for concomitant oral medication was the least important attribute to patients and physicians. Both groups were willing to accept more than a 25-percentage-point increase in the risks of severe diarrhea, fatigue, and dizziness for improvements (from 45% to 60% or 85%) in OS. Conclusions: While both patients and physicians weighted OS improvements more than the other treatment attributes, including risks, physicians tended to place lower importance on changes in risk and administration than patients. Physicians and patients should discuss potential benefits and harms when considering adjuvant RCC therapies. [Table: see text]
Patient perspectives on the impact of immune therapy on comorbid conditions in kidney cancer.
Authors: Vaishampayan Ulka N. , Staehler Michael D. , Pal Sumanta Monty , Zipperer Emma , Vaishampayan Neil , Shah Neha , Battle Dena
Published: March 2023

640

Background: Immune based regimen has rapidly become the mainstay of frontline therapy in advanced RCC. The median survival is in the range of 48-55 months and long term remissions are feasible. The impact of the therapy on other health conditions has not been studied. The immune therapy toxicities can potentially be long lasting and life changing. With the conversion of advanced RCC to a chronic disease, awareness and management of these conditions is important. With the use of immune checkpoint therapy in the adjuvant setting has made this information even more critical. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. The comorbid conditions were collected and patient perspective on changes to any medical conditions was evaluated in the survey questionnaire. Results: Patients with metastatic disease being treated with systemic therapy were included in this survey. A total of 1062 patients responded to the survey of which 399 patients self identified as being metastatic and 289 reported to be treated with immune based systemic therapy. The table includes patient characteristics. 85% respondents were from the United States. The most common condition that developed after starting immune based therapy was thyroid dysfunction as seen in 81 patients, followed by hypertension (Htn) in 50 pts, chronic kidney disease in 23 pts, heart disease in 10 patients and diabetes mellitus (DM) in 13 pts. Immune disorders developed in 26 (10%) patients. Conclusions: There is a noteworthy incidence of medical conditions emerging as a result of immune checkpoint inhibitor therapies in RCC. This information would be a starting point for studying the long term effects of immune therapy and would lead towards development of survivorship programs for renal cancer. [Table: see text]
Consideration for reclassification of pathologically upstaged T3a renal cell carcinomas.
Authors: Puri Dhruv , Wang Luke , Meagher Margaret F , Shah Aastha , Ghassemzadeh Saeed , Liu Franklin , Nguyen Mimi , Dhanji Sohail , Hakimi Kevin , Nasseri Ryan , Javier-Desloges Juan , McKay Rana R. , Derweesh Ithaar H
Published: March 2023

644

Background: Pathological upstaging to pT3a disease can occur after the surgical treatment of clinical T1 and T2 Renal Cell Carcinomas (RCCs), and this upstaging has been previously shown to be associated with poorer outcomes. With an intent to delve deeper into the disparateness in outcomes of pT3a disease, we investigated the survival of patients with an initial clinical stage of cT1, cT2 and cT3a. Methods: Using the National Cancer Database (NCDB), patients with RCC were categorized by pathological and clinical staging of RCC according to the American Joint Committee on Cancer Guidelines (AJCC). The primary outcome was measured as overall survival (OS) at the end of follow up. Five-year survival rates and Kaplan-Meier Analysis assessed the differences between cT1 → pT3a, cT2 → pT2, cT2 → pT3a, and cT3a → pT3a. Multivariable cox regression (MVA) assessed predictors OS with age, sex, ethnicity, Charlson Score, socioeconomic status, geography, tumor size histology and grade, lymph node metastasis, surgical margins, and surgery type (partial versus radical nephrectomy) as covariates. Results: 53908 patients were analyzed (10789 cT1 → pT3a, 22183 cT2 → pT2, 9676 cT2 → pT3a, 11260 cT3a → pT3a, mean follow up 62.3 months). Of all pT3a patients, 64.5% were upstaged from cT1-2. MVA for OS demonstrated Hispanic ethnicity to be protective (hazard ratio [HR]=0.88, P<0.001) and revealed different histologic risks. MVA for OS demonstrated that cT2 → pT3a (HR=1.33, P<0.001, cT1 → pT3a [ref]) and cT3a → pT3a (HR=1.35, P<0.001, cT1 → pT3a [ref]) were associated with worsened OS, and that cT1 → pT3a and cT2 → pT2 (HR=0.96, P<0.052, cT1 → pT3a [ref]) were associated with improved OS. Kaplan-Meier analysis revealed a difference in 5 year overall survival as well (cT1→pT3a 72%, cT2→pT2 77%, cT2→pT3a 61%, and cT3a→pT3a 59%, p < 0.001). Conclusions: Patients with cT1 upstaged to pT3a have similar outcomes to cT2 staged to pT2 and better outcomes than cT2 upstaged with the latter’s outcomes being more like cT3a staged to pT3a. The TNM staging system from AJCC for RCCs should consider these outcomes and adjust the grouping for RCCs accordingly.
Does the time-of-day administration of immune checkpoint inhibitors affect efficacy in patients with metastatic renal cell carcinoma? A single-center study.
Authors: Fernandez-Mañas Laia , Gonzalez Aguado Laura , Aversa Caterina , Ferrer-Mileo Laura , Garcia de Herreros Marta , Jiménez Natalia , Febrer Albert , Vernet Roger , García-Esteve Samuel , Mellado Begona , Reig Torras Oscar
Published: March 2023

681

Background: Immune checkpoint inhibitors (ICI) are the standard of care for metastatic renal cell carcinoma (mRCC). Circadian rhythm drives organisms to properly predict and react to cyclical changes in the environment, and also affects the adaptive immune response. Here, we study the relationship between time-of-day ICI administration and outcomes in mRCC patients (pts). Methods: This is a single-center retrospective study of ICI-treated mRCC pts diagnosed from January 2014 to March 2022. Day and time of each ICI infusion (inf) for each pt were obtained from the pharmacy records. Proportion of ICI inf administered after 4:30 pm (ICI430) was calculated based on a prior publication (Quian, Lancet Oncol 2021). The primary outcome was overall survival (OS), and secondary endpoints were time on treatment (TOT), time to next treatment (TNT), and overall response rate (ORR). The proportion of ICI430 as a continuous variable, and the dichotomized data (≥20% and ≥50%) were correlated with OS, TOT and TNT by Kaplan-Meier analysis and Cox regression, and with ORR by logistic regression. Results: Overall, 104 pts and 1763 inf were analyzed (Table). 48 pts were treated with 1st line (1L) ICI. 903 inf were administered (median 12 inf per pt, 1 - 111), 146 (15.6%) after 4:30 pm. 12 (25%) and 2 (4.2%) pts received ≥ 20% and ≥ 50% ICI430. Due to the small number of events (5 deaths and 15 progressions), of ICI430, and heterogeneity of treatments in 1L, we focus on pts treated with 2nd line (2L) ICI. 56 pts were treated with ICI in ≥2L. 860 inf were administered (median 8 inf per pt, 1 - 123), 180 (20.9%) after 4:30 pm. 15 (34.1%) and 9 (20.5%) pts received ≥20% and ≥50% ICI430. Pts who received ≥20% after 4:30pm, received fewer inf (7 vs. 16, p=0.022), had a worse TOT (4.3 vs. 9 m, HR 2.5, p=0.013), a trend to a worse TNT (6.3 vs. 10.5 m, HR 1.9, p=0.06) and a worse OS (16.9 vs. 56.1 m, HR 3.1, p=0.01). Similar results were obtained when using ≥ 50% ICI430 as the cut-off (TOT, 2 vs. 9m, p=0.007; TNT 4.7 vs. 10.5m, p=0.05; OS 16.9 vs. 36.6m, p=0.1), as well as higher frequency of progressive disease (85.7 vs. 21.9%, p=0.006). A significant association with OS (HR 1.02, p=0.03) was shown when analyzing ICI430 as a continuous variable, meaning a 16% increase in the risk of death for each 10% increment of ICI inf after 4:30 pm. Conclusions: Administration of ≥2L ICI after 4:30 pm is associated with poor overall survival. Our results could have a direct impact on pt survival and organization of outpatient clinics, but further research is needed. [Table: see text]
Immune checkpoint inhibitors in the peri-operative setting in renal cell carcinoma: A meta-analysis of the randomized clinical trials.
Authors: Esteban Villarrubia Jorge , Carril-Ajuria Lucía , Carretero-González Alberto , Romero Ferreiro Carmen , Álvarez Pablo , Ruiz-Vico Maria , Castellano Daniel , de Velasco Guillermo
Published: March 2023

682

Background: Localized and oligometastatic resectable renal cell carcinoma (RCC) have moderate to high rates of relapse after surgery and evidence regarding the efficacy of perioperative treatments is conflicting. The risk of relapse varies across studies and there is a need to define the benefit/risk of immune checkpoint inhibitors (ICI) in this setting to optimize their use. Methods: A meta-analysis of the randomized phase 3 trials of peri-operative treatment with anti-PD-1/PD-L1 agents or anti-PD1/antiCTL4 in combination was conducted. The primary outcomes of interest were disease-free survival (DFS) and overall survival (OS). Secondary outcomes of interest were the proportion of grade 3-4 adverse events (AE) according to CTCAE 5.0. Subgroup analyses were performed according to clinically relevant characteristics. Statistical heterogeneity assumption was evaluated by the χ²-based Cochran’s Q test and quantified with the I² statistic. All statistical analyses were performed using Stata software (StataCorp LLC), version 16. Results: Published results of 4 phase 3 trials were included, involving 3393 patients. 1695 patients received ICI (anti-PD1: 900 patients; anti-PD-L1 390 patients, antiPD1/anti-CTLA4 405 patients) while 1712 received no active treatment (1297 placebo, 415 observation). ICI did not show to increase DFS (Hazard ratio (HR) 0.84 95% CI 0.69-1.03 p 0.10) or OS (HR 0.73 95% CI 0.40-1.34 p 0.31). High-grade AEs were 2.6 times more frequent in the immunotherapy arm (OR 2.64 95% CI 1.54 – 4.68 p < 0.001) while high grade treatment-related AEs were 8 times more frequent in the experimental arm (OR 8.60 95% CI 3.23-22.91 p < 0.001). Interestingly, subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR 0.72 95% CI 0.55-0.93 p 0.01), in patients with sarcomatoid differentiation (HR 0.59 95% CI 0.403-0.88 p 0.010) and PD-L1 positive tumors (HR 0.74 95% CI 0.61-0.90 p 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs M0 patients). Conclusions: The introduction of anti-PD-(L)1 +/- anti-CTLA-4 agents in the adjuvant setting of RCC might benefit selected RCC patients, although with increased toxicity. Longer follow-up of the conducted studies is needed to establish a potential benefit in long-term survival.
Real-world prostate-specific antigen (PSA) response and disease progression among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) initiated on apalutamide (APA).
Authors: Lowentritt Benjamin H , Du Shawn , Rossi Carmine , Kinkead Frederic , Waters Dexter , Moore Bronwyn , Lefebvre Patrick , Pilon Dominic , Muser Erik
Published: March 2023

69

Background: For patients with nmCRPC, APA with androgen deprivation therapy is an important therapeutic option with demonstrated efficacy in improving metastasis-free survival (MFS), and other clinical outcomes. However, there is limited real-world information on these outcomes among patients with nmCRPC treated with APA. This study describes PSA response and MFS among patients with nmCRPC treated with APA in the United States as compared to the SPARTAN registrational trial. Methods: Clinical data from 2/2017 to 4/2022 collected from 77 community-based urology practices were used to evaluate patients with nmCRPC who received ≥1 APA dispensation (index date being the date of first dispensation). Patients were excluded if they had previously used another next-generation antiandrogen or had <12 months of pre-index clinical activity. PSA response was evaluated while on treatment and was defined as a post-index ≥90% decline (PSA90) in PSA from baseline (using the closest PSA value within 13 weeks prior to or on the index date) and was reported in patients with ≥1 post-index PSA test result by 3 months, 6 months, 12 months and overall. Disease progression was evaluated as MFS and defined as the time from index date to the occurrence of metastasis or death, whichever occurred first. Disease progression was described using Kaplan-Meier (KM) analysis by 6-month increments up to 24 months post-index. Results: A total of 406 patients with nmCRPC (mean age 78.8 years, 73% white, mean baseline PSA 9.0 ng/mL) were identified. Among 96 patients with available data, the mean (median) baseline PSA doubling time was 9.9 (7.5) months. The mean (median) treatment duration was 434 (305) days. PSA90 rates were 40% by 3 months, 51% by 6 months, 56% by 12 months, and 58% overall. KM rates for MFS were 95% at 6 months, 90% at 12 months, 82% at 18 months, and 75% at 24 months. PSA response and MFS for real-world patients were consistent with those observed from the SPARTAN trial. Conclusions: This real-world study of patients with nmCRPC demonstrates that APA treatment resulted in early, deep PSA responses, consistent with the SPARTAN trial. Moreover, MFS observed in the real-world was similar to that of the SPARTAN trial. [Table: see text]
Assessment of surgical complications in patients with metastatic clear cell renal cell carcinoma (mccRCC) receiving perioperative cabozantinib and nivolumab on Cyto-KIK clinical trial.
Authors: Runcie Karie , Ornstein Moshe Chaim , Saraiya Biren , Krishnamurthi Venkatesh , Lee Byron H , Anderson Christopher B. , DeCastro Guarionex Joel , McKiernan James M. , Dallos Matthew , Mayer Tina M. , Marron Melanie , Kulik Alexandria , Singer Eric A. , Stein Mark N.
Published: March 2023

691

Background: The perioperative safety of cabozantinib and nivolumab in mccRCC, and the optimal timing to hold cabozantinib prior to surgery, are unknown. Methods: In this phase 2 trial, patients with mccRCC are given cabozantinib (40mg daily) and nivolumab (480mg q4 weeks) for 12 weeks prior to cytoreductive nephrectomy. Post-operatively, patients resume treatment with cabozantinib and nivolumab until disease progression. A 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabozantinib and nephrectomy. Evaluable patients completed at least 10 of 14 cabozantinib doses prior to the pre-specified period of stopping pre-operative cabozantinib. Surgical complications assessed using the Clavien-Dindo classification system is a secondary endpoint of this study. Results: 16 patients have been enrolled and 14 completed nephrectomy to date. 12 (75%) of patients are male, 4 (25%) female, ages 44-77 years old with median age at diagnosis 58.5 years old. BMIs ranged from 17.8 kg/m2 to 39.3 kg/m2 with median BMI of 28.7kg/m2. 63% of patients were classified by IMDC as intermediate-risk and 37% as poor-risk disease. Dose reductions of cabozantinib occurred in 14% of patients who completed nephrectomy and cabozantinib held in 42% of nephrectomy patients during the course of treatment. Three evaluable patients completed nephrectomy within the 21-day interval and 5 within the 14-day interval after discontinuation of cabozantinib. There were no treatment-related surgical complications in patients who completed nephrectomy and there were no delays in resuming combination systemic therapy after surgery. Conclusions: Combination cabozantinib and nivolumab can be safely administered up to 14 days prior to cytoreductive nephrectomy. Clinical Trial Information: NCT04322955 Clinical trial information: NCT04322955 .
Efficacy of immune-checkpoint inhibitor (ICI) combination as a first-line (1L) therapy in metastatic renal cell carcinoma (mRCC) with sarcomatoid histology: A systematic review and meta-analysis.
Authors: Siddiqi Rabbia , Kumar Gaurav , Ijaz Hafsah , Naqvi Syed Arsalan Ahmed , Ayaz Ahsan , Riaz Zaryab Bin , Bryce Alan Haruo , Ho Thai Huu , Riaz Irbaz Bin , Singh Parminder
Published: March 2023

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Background: Sarcomatoid mRCC exhibits poor prognosis and limited response to vascular endothelial growth factor pathway inhibition. Therefore, we assessed the efficacy of ICI combination therapy in this patient population using data from contemporary trials. Methods: MEDLINE and EMBASE were searched to identify phase III randomized controlled trials (RCTs) comparing the efficacy of ICI combinations with sunitinib monotherapy in patients with sarcomatoid mRCC. Patient important outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR). Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for survival outcomes and binary outcome data for response rates (expressed as relative risk [RR] were meta-analyzed using a DerSimonian-Lairds random-effects method. Mixed treatment comparisons among different ICI combinations were made using a network-meta-analysis within the Bayesian framework. The surface under the cumulative ranking curves (SUCRA) were computed to assess the relative treatment rankings. Results: Six RCTs with a total of 618 patients were considered eligible for inclusion. ICI combination therapy was significantly associated with improved OS (HR: 0.56; 95% CI: 0.43-0.72) and PFS (HR: 0.50; 0.40-0.62), increased ORR (RR: 2.42; 1.92-3.06), and CR (RR: 4.23; 2.00-8.93) when compared to sunitinib in patients with sarcomatoid mRCC (Table). The results were consistent with Hartung-Knapp adjustment. Mixed treatment comparisons using current data revealed no statistically significant differences among different ICI combinations. However, the combination of nivolumab-ipilimumab was consistently ranked higher (rank 2 for OS, ORR, and CR) and may potentially be more efficacious than other counterparts. Conclusions: Current evidence suggests improved survival, delayed disease progression and increased response rates with the use of ICI combination therapy in patients with sarcomatoid mRCC. [Table: see text]
Association of mitochondrial metabolic activity and immune pathways with disease stage in renal cell carcinoma.
Authors: Gulati Shuchi , Shamsaei Behrouz , Vemuri Bhargav , Yang Juechen , Secic Dina , Bischoff Megan , Figueroa Julio A Landero , Plas David R. , Cunningham Tom , Meller Jarek , Czyzyk-Krzeska Maria F.
Published: March 2023

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Background: Previous large scale genomic studies have described somatic alterations that affect tumor progression. However, metabolic and immune pathway changes that occur with advancing disease stage are not well characterized. Herein, we performed transcriptomic profiling of clear-cell renal carcinoma (ccRCC) tumors across clinical stages to define these changes. Methods: TCGA Firehose Legacy cohort was used to determine differential gene expression between stage 3 ccRCCs from patients who remained disease free (S3DF) vs. those who relapsed (S3RL) within two years of nephrectomy. Single cell RNA-seq (scRNAseq) analysis was performed on primary ccRCCs from nine patients (stage 1 n=4, stage 3 n=4, metastatic n=1). Seurat V4 package and module score was used to analyze patterns of gene expression associated with tumor progression at the single cell level. Results: Transcriptomic comparison of ccRCCs from TCGA Firehose Legacy cohort revealed induction of genes encoding mitochondrial respiratory complexes and mitochondrial ribosomal proteins (MRPs) and decrease in expression of immune genes in S3RL as compared to S3DF tumors. Using a set of 23 differentially regulated mitochondrial and immune genes we established a transcriptomic signature that stratified patients into those at risk of relapse vs. not. ScRNA-seq data analysis determined increased expression of mitochondrial respiratory complexes’ gene-sets, and decreased levels of glycolytic genes and HIF targets during tumor progression from stage-I to metastatic. This was supported by spatial transcriptomics of cancer cells, which revealed clusters of cells with high mitochondrial activity and decreased MHC class I and II gene expression. Conclusions: The data support a model of progressive metabolic reprogramming from glycolysis and HIF-regulated pathways to mitochondrial respiration in parallel with diminished immune expression of antigens on cancer cells with advancing disease stage in ccRCC. Identification of targetable mitochondrial vulnerability could be a therapeutic option in patients who progress on immune checkpoint inhibitors.
Time interval between radium-223 (223Ra) therapy and Lutetium-177–prostate-specific membrane antigen (177Lu-PSMA) treatment and outcomes in the RALU study.
Authors: Rahbar Kambiz , Essler Markus , Eiber Matthias , la Fougère Christian , Prasad Vikas , Pabst Kim M. , Fendler Wolfgang Peter , Rassek Philipp , Hasa Ergela , Dittmann Helmut , Bundschuh Ralph A. , Kurtinecz Milena , Schmall Anja , Verholen Frank , Sartor A. Oliver
Published: March 2023

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Background: 223Ra and 177Lu-PSMA-617 both prolong overall survival (OS) in different mCRPC settings. The observational, retrospective study, RALU, investigated safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in patients (pts) with mCRPC. This analysis evaluated the association of time interval between 223Ra and 177Lu-PSMA treatments and safety and OS outcomes of 177Lu-PSMA. Methods: Retrospective data were collected from 2021–22 in German nuclear medicine centers for all pts receiving 177Lu-PSMA with prior history of 223Ra therapy. Time intervals were <6 months (mo) (Group [Grp]1) or ≥6 mo (Grp 2) from last 223Ra dose to first 177Lu-PSMA dose. Results: 42 pts received 177Lu-PSMA within 6 mo after 223Ra (Grp 1) and 90 pts received 223Ra ≥6 mo prior to 177Lu-PSMA (Grp 2). Baseline characteristics prior to 177Lu-PSMA therapy were, respectively: median ages 72 and 74 years; 57% and 63% with Eastern Cooperative Oncology Group performance status (ECOG PS) 1, 43% and 37% with ECOG PS 2; median prostate-specific antigen (PSA) values were 366 and 268 ng/ml, and median alkaline phosphatase (ALP) values were 133 and 149 U/L; 40% and 64% received ≥4 life prolonging therapies before starting 177Lu-PSMA. All pts had prior 223Ra; 57% and 77% received 6 223Ra injections; other prior therapies were abiraterone (60%, 77%), enzalutamide (50%, 78%), docetaxel (71%, 76%) and cabazitaxel (17%, 26%). Prior to 177Lu-PSMA, 24% and 29% of pts had visceral metastases. 45% and 52% of pts received ≥4 177Lu-PSMA cycles. From 177Lu-PSMA start to ≤30 days post last dose, 71% and 82% of pts had treatment-emergent adverse events (TEAEs) of any grade; most common were fatigue (12%, 7%), nausea (12%, 8%) and dry mouth (7%, 18%); 36% and 24% of pts had grade 3–4 TEAEs; excluding laboratory abnormalities, osteonecrosis of the jaw was the most frequent grade 3–4 TEAE (5%, 2%). Grade 3–4 laboratory abnormalities (177Lu-PSMA start to ≤90 days post last dose) are shown; treatment-related deaths were reported for 2% and 4% of pts. AEs led to treatment delays in 10% and 9% of pts. Median OS from start of 177Lu-PSMA was 12.0 mo (95% CI, 8.8–19.9) in Grp 1 and 13.2 mo (95% CI, 10.0–15.9) in Grp 2. During 177Lu-PSMA therapy, PSA response ≥50% occurred in 53% and 39% and ALP response ≥30% in 28% and 14% of pts, respectively. Conclusions: In this real-world setting, treating pts with 177Lu-PSMA within 6 mo of completing 223Ra was clinically feasible and well tolerated: no safety signals or concerns were seen. OS outcomes were similar in pts receiving 177Lu-PSMA <6 mo vs. pts receiving it ≥6 mo after completing 223Ra. [Table: see text]
Real-world combination therapy patterns in patients receiving leuprolide or relugolix for androgen deprivation therapy in 2021 (The REAL-ADT COMBO Study): Analysis from a US EMR database.
Authors: McKay Rana R. , Gandhi Raj , Yang Eric , Pruett Janis , Nwokeji Esmond , Fallick Mark
Published: March 2023

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Background: Relugolix, an oral gonadotropin releasing hormone (GnRH) receptor antagonist, was FDA approved for the treatment of adults with advanced prostate cancer (PC) in December 2020 and became commercially available in January 2021. Data from a subgroup of patients from the Phase 3 HERO study showed patients combining relugolix with enzalutamide or docetaxel had similar efficacy and safety as other cohorts in the study. However, due to limited data, some guidelines do not recommend relugolix in combination with other therapies. We evaluated real world utilization of leuprolide and relugolix in combination with other PC medications. Methods: An observational retrospective analysis was conducted using Electronic Medical Record (EMR) data. PPS Analytics data from 89 urology practices with patients represented across all 50 states in the US were analyzed. Patients with at least one record of androgen deprivation therapy (ADT) in 2021 were included. Patients whose date of ADT initiation could not be determined were excluded from this analysis. This analysis focused on the occurrence of patients with ADT as well as in combination with other PC medications. Data are reported for all patients treated with leuprolide or relugolix and stratified by new and continuing ADT use. Combination PC medications were reported for these two ADT groups. Results: In 2021, 51,735 patients were treated with ADT; 45,599 (88.1%) were treated with leuprolide and 3,096 (6.0%) patients had at least 1 prescription for relugolix. Combination PC medications (ComboPCRx) were proportionately higher in relugolix patients than in leuprolide patients (698 [22.5%] vs 8,897 [19.5%] respectively; p < 0.0001). ComboPCRx in users new to ADT was more frequent for relugolix users (342/2,169 [15.8%]) than for leuprolide users (1934/17,737 [10.9%]). In both groups, novel anti-androgens were the most frequent type of ComboPCRx. Conclusions: In this real-world EMR analysis, relugolix use in combination with other PC medication was frequently observed, for both new to ADT and continuing ADT patients. The percentage of combination therapy with PC medications was higher for relugolix users than it was for leuprolide users. These results provide insight into the real-world use of relugolix in combination with other PC medications. Further analyses are needed to make informed treatment decisions. [Table: see text]
Activity and tolerability of maintenance avelumab (AVE) immunotherapy after first-line platinum-based polychemotherapy in patients (pts) with locally advanced or metastatic squamous cell penile carcinoma: Initial results of PULSE study.
Authors: Thiery-Vuillemin Antoine , Tartas Sophie , Mourey Loic , Colomba Emeline , Borchiellini Delphine , Goujon Morgan , Lefort Felix , Topart Delphine , Barthelemy Philippe , Lauridant Geraldine , Meurisse Aurelia , Vernerey Dewi , Massard Vincent
Published: March 2023

8

Background: Metastatic squamous cell penile carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months (mo), respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods: PULSE is a national prospective multicenter open label single arm phase II trial. Thirty-two pts will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Pts will receive AVE injections 10mg/kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) from AVE initiation according to RECIST v1.1 criteria. Key secondary endpoints will include, overall survival, safety. Here we report the results of the first interim analysis (IA). Results: From September 2019 to October 2022, 14 pts has been enrolled. Within the 9 first patients involved for the IA the median age was 69.9 years; 89% of pts had an ECOG 0-1. Of them, 1 patient and 8 pts had stage 3 and 4 disease at chemotherapy initiation, respectively. Median follow-up was 5.8 [2.3-17.2] mo. Chemotherapy regimens were triplets for 5 pts (56%), containing cisplatin for 56% and a taxane for all pts. Median duration of chemotherapy was 3.7 mo [1.2; 11.7]. At AVE initiation, 5 pts (56%) had partial or complete response and 4 pts (44%) had stable disease. Median duration of AVE was 3.7 mo with a majority (83%) of discontinuation linked to disease progression. Survival data are shown in the table. No new safety signal was identified. Conclusions: PULSE is the first prospective trial exploring avelumab maintenance activity in mSCPC. After the IA the DSMB have recommended to pursue the study based on these promising results. Updated results with additional patients, longer follow-up and ancillary explorations with biomarkers analysis will be presented at the meeting. Clinical trial information: NCT03774901 . [Table: see text]