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Real-world effectiveness and treatment (tx) patterns in patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC) receiving avelumab first-line maintenance (1LM) in Japan: Results from the JAVEMACS chart review study.
701 Background: Avelumab 1LM was approved in Feb 2021 in Japan based on results of the JAVELIN Bladder 100 phase 3 trial, which showed prolonged overall survival (OS) in pts with la/mUC that had not progressed with platinum-based chemotherapy (PBC). We report the primary analysis from a chart review study of pts with la/mUC receiving avelumab 1LM in Japan. Methods: This multicenter retrospective study reviewed medical charts of pts with la/mUC who received 1L PBC and started avelumab 1LM between Feb 2021 and Dec 2023. Pt characteristics, effectiveness, and tx patterns were analyzed. Results: The study included 354 pts. At data cutoff (Jun 2024), median observation period was 14.6 mo from start of avelumab and 19.8 mo from start of 1L PBC. At the start of avelumab, median age was 73 y (range, 43-93), 261 pts (73.7%) were male, and ECOG PS was 0 in 287 (81.1%), 1 in 57 (16.1%), and ≥2 in 6 (1.7%). Primary tumor location was bladder in 179 (50.6%) and renal pelvis/ureter in 170 (48.0%). 1L PBC was gemcitabine (gem) + cisplatin (cis) in 198 (55.9%) and gem + carboplatin (carbo) in 117 (33.1%); 101 pts (28.5%) were cis eligible, and 187 (52.8%) were cis ineligible/platinum eligible. Number of PBC cycles was 1-3 in 71 (20.1%), 4 in 206 (58.2%), 5-6 in 61 (17.2%), and ≥7 in 16 (4.5%). Median time from start of PBC to start of avelumab was 19.1 wk (IQR, 15.4-24.1). At last follow-up, 68 (19.2%) were still receiving avelumab, 202 (57.1%) had received second-line (2L) tx, and 84 (23.7%) had received third-line (3L) tx. The most common 2L and 3L tx were enfortumab vedotin (EV) in 134 (66.3%) and 25 (29.8%), cis/carbo + gem in 41 (20.3%) and 13 (15.5%), and pembrolizumab in 17 (8.4%) and 37 (44.0%), respectively. OS analyses are shown in the Table. Conclusions: Avelumab 1LM seems to provide long-term OS benefits in this population of pts with la/mUC that had not progressed with 1L PBC in clinical practice in Japan. Adequate 1L PBC selection may result in long-term OS regardless of cis eligibility. Although pts were not resistant to PBC, 2L EV was more common than 2L PBC after avelumab 1LM, highlighting the evolving tx landscape. OS, median (95% CI), mo OS from start of avelumab 1LM OS from start of 1L PBC* OS from start of 2L Overall (N=354) 31.8 (24.6-NE) 38.9 (35.6-NE) - 1L PBC Gem + cis (n=198) NE (31.2-NE) 40.8 (37.6-NE) - Gem + carbo (n=117) 24.3 (19.5-30.6) 28.9 (23.9-NE) - Platinum eligibility Cis eligible (n=101) 31.2 (20.0-NE) 38.9 (26.9-NE) - Cis ineligible/platinum eligible (n=187) 31.8 (22.6-NE) 38.7 (26.3-NE) - 2L analysis set (n=202) 24.3 (20.2-31.2) 31.3 (26.3-38.7) 15.1 (13.2-20.1) EV (n=134) 31.8 (20.6-NE) 37.2 (26.6-60.6) 17.8 (11.9-NE) PBC (n=42) 23.5 (16.9-NE) 26.9 (22.2-NE) 15.1 (11.6-NE) NE, not estimable. *Population included only pts without disease progression after 1L PBC and survived to receive avelumab 1LM.
Initial biopsy results of the PATROL study: Prostate screening for people with inherited risk of developing aggressive prostate cancer.
426 Background: Germline pathogenic variants (gPV) in prostate cancer (PrCa) risk genes are associated with aggressive disease and worse outcomes. However, the degree of risk by gene, the optimal PSA thresholds for biopsy, and the utility of MRI for screening are not well characterized. Therefore, we developed the PATROL study (clinicaltrials.gov: NCT04472338), a prospective multi-center early detection study for people at risk for PrCa due to variants in PrCa risk genes. Here, we report initial biopsy results of participants enrolled to date. Methods: The primary endpoint of PATROL is to determine the positive predictive value of predefined age-adjusted PSA thresholds and prostate-specific imaging for biopsy. Key eligibility criteria include: people ≥40y with prostates that carry a gPV in one or more of 13 PrCa risk genes. Participants undergo prostate biopsy per age-adjusted PSA threshold recommendations: PSA >1.0 ng/mL if <50y; PSA >1.5 ng/mL if 50-59y; PSA >2.0 ng/mL if ≥60y). Patients are encouraged to receive a prostate MRI at baseline and/or within one year of biopsy. Clinically significant prostate cancer (csPrCa) was defined as ≥Grade Group 2 (GG2). Results: Of 291 patients enrolled in PATROL at the time of this analysis, gPVs were most frequent in BRCA2 (n=141, 48%) and BRCA1 (n=71, 24%). 55 patients have undergone biopsy, with a median age of 57 (IQR 52-66) and median PSA of 2.2 (IQR 1.2-4.4) at time of biopsy. Of these biopsies, 10 (18.2%) had GG1 disease, and 11 (20%) had csPrCa. Of the men with csPrCa, six (55%) had PSA above the PATROL age-adjusted threshold but less than standard-of-care 4 ng/ml. An additional three (27%) patients had abnormal MRI with normal age-adjusted PSA. All 11 men with csPrCa underwent definitive treatment, while 7 of the men (70%) with GG1 initiated active surveillance. In a logistic regression model adjusting for age, gPV and PSA level, having a PIRADS 4 or 5 lesion was associated with csPrCa (OR 34.3, p=0.001). Conclusions: Screening gPV carriers using age-adjusted PSA and MRI resulted in 20% of biopsies detecting clinically significant prostate cancer. Conventional PSA thresholds for biopsy would have missed more than 80% of the clinically significant prostate cancer in men with gPV. Ongoing enrollment, site expansion and longer-term follow-up in this study, along with other studies will help improve the early detection of significant prostate cancer among men with gPV. Clinical trial information: NCT04472338 .
Real-world comparison of cabazitaxel vs. 177-lutetium-PSMA radioligand therapy in metastatic castration resistant prostate cancer.
70 Background: 177-Lutetium Prostate-specific membrane antigen (Lu-PSMA) therapy is under current scientific investigation and aims to become an established part in treatment of metastatic castration resistant prostate cancer (mCRPC). However, real-world evidence in treatment comparison is scant. Methods: We relied on the FRAMCAP database and compared cabazitaxel vs. Lu-PSMA therapy in mCRPC patients regarding progression-free (PFS) and overall (OS). Sensitivity analyses addressed 2 nd to 4 th line mCRPC patients to approximate current Phase-III patient selection criteria. Results: Of 373 mCRPC patients, 14% received cabazitaxel vs. 65% Lu-PSMA vs. 21% both. Patients undergoing Lu-PSMA therapy were significantly older (median 72 vs. 66 years, p<0.01) and displayed a higher proportion of ECOG ≥2 (12 vs. 5.0%, p=0.1), relative to cabazitaxel patients. Rates of PSA50 were 32% vs. 0% for Lu-PSMA vs. cabazitaxel. In outcome analyses, significant superior median PFS was observed for Lu-PSMA vs. cabazitaxel (13.4 vs. 7.1 months, p<0.001), even after multivariable adjustment (HR: 0.38, p<0.001). Regarding OS, rates also significantly differed with median OS of 14.7 vs. 16.5 vs. 29.6 months for cabazitaxel vs. Lu-PSMA vs. both treatments (p<0.01). In sensitivity analyses of 2 nd to 4 th line mCRPC, PFS rates and median OS rates for cabazitaxel vs. Lu-PSMA vs. both therapies qualitatively remained the same compared to the entire cohort. Conclusions: In real-world setting, Lu-PSMA provides significantly better PFS and qualitatively better OS rates compared to cabazitaxel chemotherapy and should therefore be considered as a valuable treatment option for advanced mCRPC patients according to the EMA-approval. Characteristics of 296 metastatic castration resistant prostate cancer (mCRPC) patients stratified according to treatment of cabazitaxel vs. 177 - Lutetium- prostate-specific membrane antigen radioligand therapy (Lu-PSMA). Characteristic N Overall,N = 296 1 CabazitaxelN = 52 (18%) 1 Lu-PSMA,N = 244 (82%) 1 p-value 2 Age at mCRPC, years 192 71 (64, 76) 66 (58, 71) 72 (66, 78) <0.001 PSA at m CRPC, ng/ml 141 18 (6, 72) 63 (12, 144) 15 (6, 64) 0.044 Number of CRPC lines 296 3 (2, 4) 4 (3, 5) 3 (2, 4) <0.001 Cycles systemic treatment 229 3 (2, 6) 5 (3, 6) 3 (2, 6) 0.031 PSA response, % 39 20 (0, 66) 15 (0, 23) 25 (0, 68) 0.3 PSA50 39 11 (28%) 0 (0%) 11 (32%) 0.3 PSA90 39 5 (13%) 0 (0%) 5 (15%) 0.9 ECOG status at mCRPC 109 0.10 0 52 (48%) 14 (70%) 38 (43%) 1 45 (41%) 5 (25%) 40 (45%) >=2 12 (11%) 1 (5%) 11 (12%) Cardiovascular disease 183 66 (36%) 13 (35%) 53 (36%) 0.9 Gleason Score 8-10 259 181 (70%) 39 (80%) 142 (68%) 0.10 De Novo mHSPC 290 161 (56%) 33 (63%) 128 (54%) 0.2 High volume mHSPC 146 99 (68%) 24 (73%) 75 (66%) 0.5 Metastatic sites at mCRPC 130 0.8 M1a 14 (11%) 3 (13%) 11 (10%) M1b 104 (80%) 20 (83%) 84 (79%) M1c 12 (9%) 1 (4%) 11 (10%) Treatment mHSPC 126 0.034 ADT mono 25 (20%) 4 (20%) 21 (20%) ARSI 58 (46%) 4 (20%) 54 (51%) Docetaxel 34 (27%) 10 (50%) 24 (23%) Triplet 3 (2%) 1 (5%) 2 (2%) Other 6 (5%) 1 (5%) 5 (5%) Treatment 1st line mCRPC 296 <0.001 ADT mono 29 (10%) 6 (12%) 23 (9%) Chemotherapy 53 (18%) 19 (37%) 34 (14%) Lu-PSMA 28 (10%) 0 (0%) 28 (11%) ARSI 163 (55%) 26 (50%) 137 (56%) PARPi +/- ARSI 1 (0.3%) 0 (0%) 1 (0.4%) Radium 20 (7%) 0 (0%) 20 (8%) None/Other/NA 2 (1%) 1 (2%) 1 (0.4%) Treatment 2nd line mCRPC 296 <0.001 Chemotherapy 69 (23%) 27 (52%) 42 (17%) Lu-PSMA 73 (25%) 0 (0%) 73 (30%) ARSI 114 (39%) 25 (48%) 89 (36%) PARPi+/- ARSI 5 (2%) 0 (0%) 5 (2%) Radium 13 (4%) 0 (0%) 13 (5%) None/Other/NA 22 (7%) 0 (0%) 22 (9%) 1 Median (IQR); n (%). 2 Wilcoxon rank sum test; Fisher’s exact test; Pearson’s Chi-square test. PSA: Prostate-specific antigen, ECOG: Eastern Cooperative Oncology group, mHSPC: metastatic hormone-sensitive prostate cancer, ADT: Androgen deprivation therapy, ARSI: Androgen receptor signaling inhibitor, PARPi: poly-(ADP-ribose)-polymerase inhibitors, NA: Unknown.
Mevrometostat (PF-06821497) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate: The phase 3, randomized MEVPRO-1 study.
TPS288 Background: Resistance to androgen receptor (AR) pathway inhibitors (ARPI; e.g., abiraterone, enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) may be driven by preservation of AR signaling through various mechanisms. Enhancer of zeste homolog 2 (EZH2) is implicated in the pathogenesis of prostate cancer and ARPI resistance. Combining ARPI with therapies that modulate alternative signaling pathways, including epigenetic modifiers such as EZH2, could be a promising treatment approach to overcome resistance. Mevrometostat (PF-06821497) is a potent and selective small molecule EZH2 inhibitor. Results from the dose-escalation period of a phase 1 study (NCT03460977) showed promising activity for mevrometostat combined with enzalutamide, with a manageable adverse-event profile in abiraterone-exposed patients with mCRPC (Schweizer MT, et al. J Clin Oncol . 2024;42(16_suppl):5061). The current trial aims to evaluate radiographic progression-free survival (rPFS), overall survival (OS), and safety of mevrometostat plus enzalutamide compared with standard of care in patients with mCRPC previously treated with abiraterone. Methods: MEVPRO-1 (NCT06551324) is a global, open-label, phase 3 trial in patients with mCRPC aged ≥18 years with progression on/after ≥12 weeks abiraterone, castration testosterone levels ≤50 ng/dL, ECOG performance status 0–2, and life expectancy ≥6 months. Approximately 600 patients will be randomized 1:1 to receive mevrometostat (875mg BD with food) with enzalutamide (160mg QD), or physician’s choice of enzalutamide (160mg QD) or docetaxel (75mg/m 2 intravenously every 21d). Randomization will be stratified by previous docetaxel in metastatic castration-sensitive setting, physician’s choice of comparator (enzalutamide/docetaxel), and presence of hepatic metastases. The primary endpoint is BICR-assessed rPFS per RECIST 1.1 (soft tissue) and PCWG3 (bone) assessed by blinded central radiology review. Key secondary endpoint is OS. Secondary endpoints include anti-tumor activity, safety, pharmacokinetics, ctDNA, and patient-reported outcomes. Stratified log-rank P -values, HRs, and 95% CIs will be estimated using a stratified Cox proportional hazard model, and Kaplan–Meier analysis will summarize time-to-event endpoints. Clinical trial information: NCT06551324 .
Association between proto-oncogene N-RAS transcript level and overall survival in node-negative muscle-invasive urothelial bladder carcinoma.
820 Background: Prognostication of urothelial bladder carcinoma relies on clinicopathologic factors including histology, TNM stage and genomic profiles. The prognostic value of tumor subtyping based on gene expression signature clustering has been proposed, but their clinical value remains uncertain. Here, we retrospectively review node-negative muscle-invasive urothelial bladder carcinoma RNA-Seq data and demonstrate that “low” mRNA expression of proto-oncogene N-RAS is associated with significantly superior overall survival (OS). Methods: The Cancer Genome Atlas (TCGA) Pan-Cancer project batch-corrected primary tumor RNA-Seq expression profiles of 114 urothelial bladder carcinoma cases (pT2-4a pN0 M0, n=97; any pT pN1 M0, n=17) and their associated clinical data were retrieved from the cBioPortal. Cohort median was used as a reference to determine “high” vs. “low” transcript levels of N-RAS gene. Log-rank Kaplan-Meier was performed for survival analysis. Two-tailed Mann-Whitney test was performed for group comparison. Results: In node-negative disease group, “low” N-RAS expression (n=58) was associated with significantly superior 5-year OS compared to patients with “high” N-RAS expression (n=39) with hazard ratio (HR) for death at 0.41 (95% CI 0.19-0.86, p=0.007). N-RAS expression-associated differential OS was independent from age group (≥67 vs. <67), gender, T stage (T2 vs. T3-4a), cisplatin-based chemotherapy exposure or underlying TP53, RB1, FGFR3, RAS mutation. However, in patients with “low” N-RAS expression the 5-year OS of those who received cisplatin-based chemotherapy (n=5) was significantly superior compared to those who did not (n=53) with HR for death at 0.26 (95% CI 0.07-0.98, p=0.047). “High” N-RAS expression group was associated with higher CD274 (PD-L1) mRNA expression (x3.9 higher median value, p<0.0001) and larger portion of patients with ≥10 mut/Mb tumor mutational burden (40% vs. 23%) compared to “low” N-RAS expression group. In node-positive disease group, N-RAS expression-dependent differential OS was not present. Conclusions: In node-negative muscle-invasive urothelial bladder carcinoma, “low” N-RAS expression was associated with superior OS which was most pronounced in patients who received cisplatin-based chemotherapy. “High” N-RAS expression was associated with higher PD-L1 mRNA expression and tumor mutational burden. We speculate that N-RAS transcript level might be a novel biomarker for prognostication and treatment response as an adjunct to TNM stage. Further investigation is warranted.
Racial disparities in incidence-based mortality and survival outcomes in testicular cancer in adolescent and young adults.
650 Background: Testicular cancer is the most common malignancy in males aged 15-35, with increasing incidence worldwide. Despite overall high survival rates, significant outcome disparities persist across race, socioeconomic status, and geographic location. Addressing these disparities is crucial to ensure equitable access to early diagnosis, treatment, and supportive care for all patients. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) 17 Research database program was utilized to obtain the annual percentage change (APC) in incidence of testicular cancer from 2000 - 2021 for patients aged 15 - 39 years (AYA group). Patient characteristics were expressed in proportions (%). The Kaplan Meier method was used to determine overall survival (OS) and cancer-specific survival (CSS). Cox regression was performed to determine predictors of survival. A p-value ≤0.05 was considered statistically significant. Results: A total of 19680 met our specified criteria and were included in our studies. We excluded cases with unknown race, and non testicular cancer cases. Our reference race was Hispanics. Compared to Hispanics. Non hispanic American Indian/Alaska Native had HR 1.696, (CI 1.290-2.229, p < 0.001, Non hispanic Asian/Pacific Islander had HR 0.880 (CI 0.712-1.087, p = 0.234), Non Hispanic Blacks had HR 1.608 (CI 1.267-2.039, p < 0.001), Non Hispanic Whites had HR 0.770 (CI 0.682-0.870, p < 0.001). Conclusions: Our study reveals significant racial disparities in testicular cancer survival outcomes with Non hispanic American Indian/Alaska Native and Non Hispanic Blacks having higher mortality risk. These findings highlight the need for targeted interventions to address survival disparities in testicular cancer across different racial and ethnic groups within the AYA demographic.
Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with androgen receptor pathway inhibitors in patients with metastatic hormone-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01).
TPS279 Background: PARP inhibitors (PARPi) in combination with androgen receptor pathway inhibitors (ARPIs) are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). PARPi utilization in earlier lines of treatment may result in greater magnitude of benefit. Saruparib is a potential best-in-class PARPi, which selectively inhibits and traps PARP1, has minimal effect on PARP2, and hence may offer an improved therapeutic window compared with currently approved nonselective PARPi. The efficacy and safety of saruparib plus ARPIs for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and mCRPC are being assessed in the phase I/IIa PETRANHA study (NCT05367440). The phase III EvoPAR-Prostate01 study (NCT06120491) is evaluating the efficacy and safety of saruparib plus physician’s choice of ARPI (abiraterone, darolutamide, or enzalutamide) compared with placebo plus physician’s choice of ARPI in participants with mHSPC. Methods: This is a 2-cohort, 2-arm, randomized, double-blind, placebo-controlled, multicenter global study. Key eligibility criteria include age ≥18 years, histologically confirmed mHSPC ( de novo or recurrent low- or high-volume disease), ECOG PS 0-1, and confirmed, prospectively defined homologous recombination repair gene mutation (HRRm) status (defined by the presence/absence of pathogenic/likely pathogenic mutations in ≥1 of the genes BRCA1 , BRCA2 , ATM , CDK12 , PALB2 , RAD51B , RAD51C , RAD51D , and BARD1 ). Participants must be receiving androgen deprivation therapy throughout the study or have undergone bilateral orchiectomy, and must be suitable for treatment with ARPIs. Key exclusion criteria include prior therapy with PARPi, prior chemotherapy or ARPIs in the mHSPC setting (prior ARPIs for localized disease permitted), and history of, or suspected, myelodysplastic syndrome/acute myeloid leukemia. Participants are allocated to either the HRRm or non-HRRm cohort based on prospective testing of both tumor tissue and circulating tumor DNA. Participants are randomized 1:1 to receive saruparib plus physician’s choice of ARPI or placebo plus physician’s choice of ARPI. Treatment continues until disease progression, unacceptable toxicity, or participant-initiated withdrawal. The primary endpoint is radiographic progression-free survival (rPFS), with overall survival (OS) a key secondary endpoint. Planned statistical analyses of rPFS and OS will be conducted within each cohort using a stratified log-rank test. Approximately 1,800 participants (550 HRRm; 1,250 non-HRRm) will be randomized. Enrollment began in November 2023 and is ongoing. Clinical trial information: NCT06120491 .
A phase II clinical study of camrelizumab plus apatinib in combination with stereotactic body radiotherapy (SBRT) for advanced non-clear cell renal cell carcinoma (nccRCC).
557 Background: The efficacy of targeted therapy alone in the treatment of advanced nccRCC remains unsatisfactory, but its combination with immunotherapy and/or SBRT is worth exploring. In this study, we aimed to investigate the safety and efficacy of camrelizumab plus apatinib combined with SBRT for advanced nccRCC. Methods: This is a single-arm, phase Ⅱ study enrolling recurrent/metastatic nccRCC patients (pts), for whom the cytoreductive SBRT (defined as the lesions receiving SBRT≥50% of the tumor burden) can be safety applied (ChiCTR2000034727). No liver or brain metastasis was allowed. Eligible pts received camrelizumab (200mg, day 1) (for wgt <= 40kg, 3mg/kg) and apatinib (250mg, once daily, day 1-14) in a 2-week cycle. Cytoreductive SBRT (20-45 Gy, 1-5 fractions) was performed between the 1 st and the 3 rd administration of camrelizumab. The primary endpoint of this study was the objective response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), safety, and quality of life. Results: From Oct. 26, 2020, and Sep. 6, 2024, a total of 37 pts were enrolled, and 32 pts were evaluable for efficacy after SBRT. Among them, 11 (34.4%) had Xp11.2 translocation, 10 (31.3%) pts had papillary, 5 (15.6%) had fumarate hydratase-deficient, 2 (6.3%) had chromophobe, 1 (3.1%) had collecting duct, 1 (3.1%) had sarcomatoid, and 2 (6.3%) had unclassified histology. 3 (9.4%) pts were local-reginal recurrent, whereas 14 (43.8%) were oligometastatic, and 15 (46.9%) were multiple metastatic. 31 (96.9%) pts were IMDC intermediate or high risk, and 10 (31.3%) pts received at least one prior systemic therapy. With a median follow-up time of 18.9 months, 23 (71.9%) pts achieved ORR, of which 12 (37.5%) pts had complete response and 11 (34.4%) pts had partial response. The DCR was 93.8%, and the median PFS was 19.0 months. The most common adverse events (AEs) of any grade were creatinine increased (n = 21, 65.6%), followed by anemia (n = 19, 59.4%), aspartate aminotransferase (AST) increased (n = 19, 59.4%), proteinuria (n = 19, 59.4%), and hypertension (n = 13; 40.6%). Grade 3 AEs occurred in 11 pts (4 proteinuria, 4 AST increased, 2 blood bilirubin increased, 2 rash, and 2 neutrophil counts decreased). The most common AEs after SBRT were nausea (n = 10; 31.3%). No grade 4-5 AEs occurred. Furthermore, the proportion of CD4+ and CD8+ lymphocytes in peripheral blood increased after SBRT and dropped to baseline levels after the 4 th and the 8 th cycle of camrelizumab, respectively. To the opposite, the proportion of CD19+ lymphocytes decreased after SBRT but continued to increase after the 2 nd circle of camrelizumab. Conclusions: Camrelizumab plus apatinib combined with SBRT showed promising antitumor activity and manageable toxicity in pts with recurrent/metastatic nccRCC. Clinical trial information: ChiCTR2000034727 .
Management of relapsed primary retroperitoneal (RP) germ-cell tumor (GCT) after front-line chemotherapy.
637 Background: Primary RP GCT represents a rare subset of extragonadal GCTs. While front-line therapy remains similar to gonadal GCT, there is limited data on management of relapsed disease for these patients (pts). Here, we describe management and outcomes of pts with relapsed primary RP GCT. Methods: The prospectively maintained Indiana University testicular cancer database was queried for patients with primary RP GCT who relapsed after first-line therapy between 1990-2024. Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Survival outcomes based on type of second-line chemotherapy was compared using the log rank test. Results: 53 pts were included in the analysis. Median age at diagnosis was 33.7yrs (17.4-67.9). Primary tumor pathology was non-seminoma in 75.5% and seminoma in 24.5%. Predominant histology was seminoma (30.2%), mixed (26.4%), choriocarcinoma (17.0%), yolk sac tumor (13.2%), embryonal (9.4%), teratoma (3.8%). Other metastasis sites included pulmonary (56.6%), liver (35.9%), posterior mediastinum (15.1%), pelvic lymph nodes (13.2%), brain (13.2%), bone (9.4%). IGCCCG risk was good in 30.2%, intermediate in 15.1%, and poor in 54.7%. First-line chemo was BEPx4 (54.6%), VIPx4 (11.3%), BEP x3 (7.5%), EPx4 (7.6%), BEPx2 + HDCTx2 (2.0%), and other (17.0%). All 53 pts had progression of disease after first-line chemo. 44 received salvage chemotherapy, 5 received RPLND, 2 other salvage surgery, 1 radiation, and 2 received no salvage therapy. Salvage chemo was HDCT for 69.8% vs. standard salvage chemo for 30.2%. For pts treated with HDCT, 83% completed 2 cycles. 46.7% of those treated with HDCT progressed afterward. Of pts who had salvage RPLND, 3 were found to have teratoma and 2 had active GCT. 2 pts had other salvage surgery; 1 had thoracotomy with GCT and 1 had craniotomy with GCT. At time of last follow-up, 28.3% of all pts were alive with NED, 11.3% were alive with disease, 13.2% were lost to follow-up, and 47.2% had died of disease. The table lists PFS and OS by salvage chemo type. Conclusions: Patients with relapsed primary RP GCT seem to have worse outcomes compared with historical results from relapsed gonadal GCT. A subset of patients with relapsed primary RP GCT are curable with salvage therapy. Survival outcomes by salvage chemotherapy received. HDCT N=30 Standard dose chemo N= 14 p-value 2-yr PFS 47.7% (95% 28.7-64.5) 31.8% (95% 7.7-59.9) p=0.18 2yr OS 53.8% (95% 34.0-70.0) 68.6 (95% 30.5-88.7) p=0.84
Metastases-directed therapy in addition to standard systemic therapy in oligometastatic castration resistant prostate cancer: A randomized phase II trial (GROUQ-PCS 9).
22 Background: Metastases directed therapy (MDT) in metachronous hormone sensitive prostate cancer (mHSPS) patients has been shown to delay systemic therapy and to a lesser extent improve oncological outcome. To date there has not been strong data to suggest benefit of MDT in castration resistant prostate cancer (CRPC). In this multi-centric randomized phase II trial, we sought to determine the benefit of stereotactic body radiotherapy (SBRT) in oligometastatic CRPC (omCRPC) patients. Methods: PCS-9 was originally designed as an adaptive randomized phase II/III trial conducted across 13 sites in Canada. Given that ARPIs became the standard of care in mHSPC, the study was stopped at the phase II level after 100 mCRPC patients, with 5 or less metastatic sites, were recruited. Patients were randomly assigned in a 1:1 ratio to androgen deprivation therapy (ADT) + enzalutamide (Enza), arm-1 or ADT + Enza + SBRT to the conventionally (CT/MRI/bone scan) identified oligometastatic sites, arm-2. The primary endpoint was radiological progression free survival (rPFS), defined as radiological progression or death from any cause. Results: Of the 100 omCRPC patients, 48 were randomized to ADT+Enza and 52 to ADT+Enza+SBRT. There was no difference in patient or disease characteristics. One to three metastases occurred in 89.6% of arm-1 and 84.6% of arm-2, while visceral involvement accounted for 2.1 and 5.8%, respectively. The addition of SBRT doubled the median rPFS compared to ADT and Enza alone. rPFS was 4.6 years in the SBRT group and 2.3 years in the ADT and Enza arm, a 50% risk reduction (HR: 0.5 with 95% CI, 0.28-0.88; p=0.017). Similarly, biochemical progression free survival (bPFS) was 4.5 years for the SBRT arm and 2.6 years for ADT and Enza alone arm, a 44% risk reduction (HR:0.56 95% CI, 0.31-0.99 p=0.0425). At the time of this analysis there was a 27% risk reduction of death with the addition of SBRT (HR:0.73; 95% CI, 0.33-1.64; p=0.463), however the median OS had not been reached for either arm. Time to subsequent therapy was significantly delayed by the addition of SBRT. The median time to subsequent therapy was 5.1 years for the SBRT arm vs. 3.8 years for the ADT + Enza alone arm, a risk reduction of 48% (HR:0.52; 95% CI, 0.27-0.047; p:0.047). There was no difference in adverse event between the arms including fatigue, hypertension and fracture. Only 4 patients in the SBRT arm reported transient pain flare at the SBRT site and one patient had acute asymptomatic pneumonitis. Conclusions: The addition of SBRT to oligometastatic sites in mCRPC significantly improved rPFS, improved bPFS and delayed the time to next line of therapy. Although OS remains immature, there was numerical reduction in the risk of death. These results strongly suggest that SBRT to oligometastatic sites is beneficial and should be considered in patients with oligo-metastatic CRPC. Clinical trial information: NCT02685397 .
Application of ML models to predict postoperative outcomes in renal cell carcinoma.
463 Background: Accurately predicting postoperative outcomes, such as major and minor complications, readmissions, and mortality, enables personalized preoperative planning, informed decision-making, and improved perioperative management. In this study, we utilized a machine learning (ML) model to predict these outcomes in RCC patients undergoing nephroureterectomy, radical nephrectomy, partial nephrectomy, and other excision procedures on the kidney using data from the National Surgical Quality Improvement Program (NSQIP; 2016-2021). Methods: A gradient-boosted tree (GBT) model was developed and trained to predict the primary outcomes of interest: major complications, minor complications, 30-day readmission, and mortality. The NSQIP dataset provided a robust source of patient data, encompassing a wide array of variables, including demographic information, preoperative health status, comorbidities, intraoperative factors, and postoperative laboratory results. The model's performance was rigorously evaluated using various measures, such as AUROC, generalized R-square, MIS classification rate, etc. The model's predictions were validated using separate training (70%) and validation (30%) cohorts to ensure generalizability and applicability in diverse patient populations. Results: In the analysis, 36,284 cases were included. The GBT model demonstrated substantial predictive power across all four outcomes. In predicting mortality, the model achieved an AUROC of 0.98 in the training and 0.80 in the validation set, with a misclassification rate of 0.68%. The prediction of major complications was also robust, with AUROC of 0.94 in the training set and 0.91 in the validation set, accompanied by a misclassification rate of 2.2%. Similarly, the model's performance in predicting minor complications and 30-day readmissions was strong, with AUROC values of 0.70 and 0.66, respectively, in the validation sets. Among the most influential predictors identified by the model were age, diabetes, sepsis, bleeding disorders, ASA classification, and preoperative albumin levels. These factors consistently contributed to the model's accuracy across the different outcome measures. BMI was among the top 15 predictors for all four outcomes in GBT analysis. Conclusions: Our study demonstrated that using a national registry, ML models can accurately predict postop outcomes among patients with RCC. By integrating a wide range of patient-specific variables, the model offers a powerful tool for clinicians to identify high-risk patients and tailor perioperative care accordingly. These findings support broader ML adoption in surgical decision-making to enhance patient safety and optimize outcomes. Post-op complications in RCC by BMI category. BMI<30 BMI≥30 p-value Mortality 115 (0.64) 98 (0.54) 0.22 Major 580 (3.21) 607 (3.33) 0.49 Minor 798 (4.41) 998 (5.48) <0.0001 30-Day Readmission 1055 (5.83) 1045 (5.74) 0.70
A clinical trial evaluating the efficacy and safety of disitamab vedotin plus tislelizumab combined with re-TURBT in the treatment of HER-2-high expression (2+-3+) non-muscle invasive bladder cancer at high-risk and very high-risk.
TPS895 Background: Current studies indicate that the combination of Disitamab Vedotin and PD-1 inhibitors can enhance the efficacy of systemic therapy in patients with HER2-positive urothelial carcinoma, with an acceptable safety profile. However, the evidence supporting its use in high-risk and very high-risk NMIBC remains limited. And several clinical guidelines recommend a re-TURBT for high-risk NMIBC patients, as it has been shown to significantly reduce the 5-year recurrence and progression rates.Therefore, this study aims to evaluate the efficacy and safety of the triplet regimen of Disitamab Vedotin, Tislelizumab (a PD-1 inhibitor), and re-TURBT in patients with HER2 IHC 2+ or 3+ high-risk and very high-risk NMIBC. Methods: Patients diagnosed with high-risk and very high-risk NMIBC, based on medical history, clinical presentation, imaging examinations (such as MRI with plain and enhanced scanning), and transurethral resection for tissue pathological biopsy, are included in the "case screening process".After excluding surgical contraindications, TURBT is performed; postoperative tissue pathological examination confirms NMIBC, and patients with immunohistochemical results of HER2 as 3+ or 2+ enter further screening. Referring to the AUA guidelines, high-risk and very high-risk NMIBC are included in subsequent analysis, where those who meet the inclusion criteria of this study, excluding the exclusion criteria, and who have recovered well after the initial TURBt and are assessed to be able to complete a second TURBT within six weeks are considered as the final candidates for enrollment.Eligible patients for single-arm enrollment (N=40) will receive Tislelizumab (200mg) + Disitamab Vedotin (120mg for weight ≤60Kg or 2.0mg/Kg for weight ≥60Kg) the day after the initial TURBT, to be repeated every 3 weeks (Q3W). Patients are also scheduled to undergo a second TURBT within 6 weeks, and after the surgery, they will continue with three more courses of Tislelizumab + Disitamab Vedotin (Q3W) until the end of the 3-year follow-up period. The primary endpoint for evaluation in this study phase is the 1-year event-free survival rate (EFS),which is defined as the possibility of patients have not experienced any events for at least 12 months after receiving treatment, including death, disease progression, switch to chemotherapy, addition of other treatments, fatal or intolerable side effects, etc. Clinical trial information: NCT06630871 .
A phase I/II study of neoadjuvant, intra-arterial administration of (177Lu)lutetium vipivotide tetraxetan in subjects with high-risk, localised or locally advanced prostate cancer (LUPUS).
TPS431 Background: The recent LuTectomy trial suggested that intra-venous [177Lu]Lu-PSMA-617 prior to surgery in men with high-risk localised or locally advanced prostate cancer (HRCaP) is safe and effective. We hypothesise that intra-arterial infusion will further enhance target lesion uptake and efficacy without compromising safety. LUPUS is the first trial investigating (177Lu)Lutetium vipivotide tetraxetan intra-arterial infusion and will help to further evaluate if there is a role for neoadjuvant radioligand therapy in HRCaP. Methods: Phase I/II study of neoadjuvant, pre-surgical (177Lu)Lutetium vipivotide tetraxetan as intra-arterial infusion in men with HRCaP who are candidates for radical prostatectomy (EU CTR 2022-500838-28-00). Intra-arterial perfusion is performed via a catheter into A. iliaca interna without concomitant embolization. In the first cohort, 10 patients will receive one cycle of 200 mCi (7.4 GBq) (177Lu)Lutetium vipivotide tetraxetan followed by radical prostatectomy 6 weeks thereafter. If less than 4 out of 10 patients have to delay surgery or suffer from CTCAE Grade ≥3 adverse events (AEs) due to the treatment, 10 additional patients will be included and receive one cycle of 400 mCi (14.8 GBq) (177Lu)Lutetium vipivotide tetraxetan. Enrolment began in September 2024. Primary endpoints are AEs and days of delay of scheduled surgery related to intra-arterial (177Lu)Lutetium vipivotide tetraxetan therapy. Secondary endpoints are PSA-response and pathological response. Other endpoints include imaging changes, changes in quality of life and dosimetry. Clinical trial information: EU Clinical Trial no.: 2022-500838-28-00 .
PPARG protein expression in advanced urothelial carcinoma and selection for response to FX-909, a first-in-class PPARG-targeting agent.
856 Background: FX-909, a PPARG inverse agonist, is being evaluated in a first-in-human, dose escalation and expansion study in patients with advanced urothelial carcinoma (UC; NCT05929235). PPARG drives development of UC and its expression is associated with the luminal lineage, which accounts for ~65% of all advanced UC patients 2 . An IHC prototype assay was developed to detect PPARG expression in formalin-fixed paraffin-embedded UC tissues. Our data show that PPARG protein expression correlated with PPARG RNA expression in a retrospective cohort of archival tissue from high-grade localized UC. Methods: Commercial antibodies, clones C26H12, K.242.9 and E-8, were tested and validated using UC and control normal tissues. The E-8 clone was selected for further development based on demonstration of good specificity, sensitivity, range, and linearity. Specificity of the PPARG staining was demonstrated in cell lysates, where PPARG expression level was confirmed by Western blot (HEK293, BC3C, UMUC9, and RT112). Assay performance was evaluated in a cohort of 25 high-grade localized, stage III-IV UC patient samples. Semi-quantitative analysis [percent (%) tumor score and H-score] was conducted by a pathologist. Gene expression values from RNAseq were normalized by transcripts-per-million (TPM). Molecular classification was performed using non-negative matrix factorization rank 5 following the Robertson method 3 derived from RNAseq. Results: The E-8 clone detected a broad range of PPARG expression, with a predominantly nuclear staining pattern at staining intensities from 0 to +3. Each sample exhibited different staining intensities, highlighting the heterogeneity of PPARG expression. Eighty-eight percent of cases showed PPARG expression in more than 50% of their tumor cells (22 out of 25). H-scores varied from 0 to 270 (Median H-Score = 146), where 64% of the cases showed a moderate PPARG expression with H-scores ranging between 100 and 200. PPARG protein expression quantitated based upon the % tumor area with 2+ or greater staining correlated with RNA expression levels (Spearman correlation coefficient r = 0.66; p-value <0.01). Similarly to previous data 2,5 , 52% of the cases in this cohort were of luminal lineage. The median RNA expression level of PPARG was significantly higher in the luminal subgroup compared to the non-luminal subgroup (6.0 Log2[TPM+1] vs 3.53 Log2[TPM+1], p <0.01). Conclusions: These data show the IHC assay is sensitive and specific for the detection of PPARG expression in advanced UC with utility to identify patients with potential to respond to FX-909, a first-in-class PPARG-targeting agent 4 . 1. Sims R, AACR 2023, Fl; 2. Motley W, et al. EORTC 2022; 3. Robertson AG, et al. Cell 2017; 4. Iyer G, et al. ASCO GU 2024, CA; 5. Kirov S, AACR-NCI-EORTC 2023, MA.
Predicting long term outcomes following radical prostatectomy using a validated pathology-based multimodal artificial intelligence biomarker.
364 Background: Over the past decade, multiple biomarkers have been developed and validated to improve precision of prostate cancer prognosis estimation. However, these require access to archival tissue and central laboratory processing for RNA extraction, and as a result are labor-intensive and expensive. Deep learning models based on image analysis of standard clinical pathology slides may offer similar accuracy with much improved access and lower cost. Multimodal artificial intelligence (MMAI) models (Artera, Los Altos, CA) have previously been validated to prognosticate as well as predict response to intensified treatment among patients undergoing radiation therapy and have been endorsed in the NCCN prostate cancer guidelines. We determined the accuracy of an MMAI model in prognosticating outcomes after radical prostatectomy (RP) using tissue microarray (TMA) specimens. Methods: We previously built a TMA from 424 mostly low- to intermediate-risk RP cases with rich clinical annotation and long-term follow-up. We scanned this TMA at high resolution and determined MMAI (scored 0 to 1) and Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S, scored 0-12) scores. We performed logistic regression to determine the MMAI’s score association with adverse pathology (pT≥3a and/or grade group ≥3), and Cox proportional hazards regression to determine the independent ability of the MMAI score to predict biochemical recurrence (two PSA tests ≥0.2 ng/ml or any second treatment) and metastasis after RP. Odds ratios (OR) and hazard ratios (HR) were determined per 0.1 increase in MMAI score. Results: The TMA was successfully segmented and images and MMAI scores were able to be generated for 414 (98%) of cases. Median (IQR) follow-up was 13.2 (7.8-18.3) years. By CAPRA-S, 273 (66%), 114 (28%), and 24 (6%) were low (0-2), intermediate (3-5), and high (≥6) risk, respectively. Recurrence-free and metastasis-free survival were 74% and 96% at 10 years, respectively. Median (IQR) MMAI risk scores were 0.25 (0.18-0.33). On logistic regression, the MMAI score was significantly associated with risk of adverse pathology (OR: 1.05, 95% CI 1.03-1.07, p<0.01). On Cox regression adjusting for CAPRA-S, MMAI risk score was significantly associated with risk of both recurrence (HR 1.04, 95% CI 1.02-1.06, p<0.01) and metastasis (HR 1.05, 95% CI 1.02-1.07, p<0.01). Conclusions: In this cohort of largely lower-risk RP patients, the MMAI score derived from RP TMA samples —originally developed among radiation therapy patients on prostate biopsy samples—adds independent prognostic information above a well-validated multivariable clinical risk model. The MMAI platform allows for rapid, non-destructive analysis of standard pathology slides and should compare favorably to RNA-based platforms in terms of access, speed, and cost.
A first-in-human phase 1 study of LY3866288 (LOXO-435), a potent, highly isoform-selective FGFR3 inhibitor (FGFR3i) in advanced solid tumors with <i>FGFR3</i> alterations: Initial results from FORAGER-1.
662 Background: Activating alterations in FGFR3 (most commonly S249C) occur in 15-20% of metastatic urothelial cancers (mUC) and <5% in other solid tumors. Erdafitinib, a pan FGFR1-4 inhibitor, improves survival in 2L FGFR3 -altered mUC but has dose limiting toxicities (DLTs) driven by off-target FGFR1/2/4 inhibition. LY3866288 is an oral, potent, isoform-selective, small molecule FGFR3i designed to limit off-target toxicities with preserved activity against acquired FGFR3 resistance mutations. Here we report initial clinical data from the phase 1 dose escalation cohort of LY3866288in FGFR3 -altered advanced solid tumors. Methods: Adults with advanced or metastatic solid tumors with an FGFR3 or FGFR3 ligand alteration (tumor or blood) that progressed on available standard therapies, ECOG PS ≤1, and RECIST v1.1 evaluable (including non-measurable) disease were eligible. Dose escalation used a single-patient accelerated design followed by mTPI-2 method. Key endpoints were safety, PK, and antitumor activity. Serial plasma samples were collected for ctDNA analysis. Results: As of 27 Aug 2024, 101 patients (pts) were treated at 10 dose levels (DLs) of LY3866288 (6 mg QD – 400 mg BID). Median age was 67 (range, 26-93), 69% ECOG PS 1, and 70% had mUC. Median lines of prior therapy was 3 (range, 1-9), including prior FGFRi in 23%. LY3866288 consistently demonstrated trough concentrations that exceeded IC 90 for FGFR3 S249C at DLs ≥200 mg BID. No significant differences in exposures were observed in pts with moderate renal insufficiency (eGFR 30-49 ml/min). No DLT was observed at any DL. At DLs ≥200 mg BID, the most common treatment-emergent AEs (TEAEs) were diarrhea (67%), hyperphosphatemia (28%), fatigue (23%), increased ALT (22%), and AST (22%); most (68%) TEAEs were grade 1/2. TEAEs associated with poor tolerance and compliance to erdafitinib (retinopathy, onycholysis, and hand-foot syndrome) were ≤5% and low grade. Treatment-related AEs (TRAEs) led to dose reduction in 5% of pts and none were associated with discontinuation. In mUC pts with an activating mutation/fusion dosed at ≥200 mg BID, the objective response rate (ORR) was 42% (14/33; 10 confirmed as of 6 Sep 2024, 4 ongoing and pending confirmation); responses were observed in both mutations (Y373C, S249C, R248C, S371C) and fusions (TACC3). In mUC pts previously treated with an FGFRi, the ORR was 45% (5/11). One pt each with NSCLC (S249C) and biliary tract cancer (TACC3) also achieved a PR. 14/16 PRs (88%) are ongoing. Decreases in FGFR3 ctDNA VAF occurred in 12/13 pts (92%) with available results at cycle 2 or 3, of which 8 achieved clearance (5 with PR; 3 with SD). Conclusions: LY3866288 is well-tolerated with robust clinical activity at multiple DLs, including in erdafitinib refractory mUC. Randomized dose optimization is ongoing and updated results will be presented. Clinical trial information: NCT05614739 .
PSMA PET vs. pelvic MRI in biochemically recurrent prostate cancer.
40 Background: After primary definitive therapy of localized prostate cancer with either radical prostatectomy or radiation therapy, up to 50% of patients will experience biochemical recurrence (BCR) of disease. The objective of this descriptive, retrospective analysis is to compare the performance of PSMA PET/CT and pelvic MRI in BCR and investigate the added value of their combined use in this patient population. Methods: Patients with BCR who underwent PSMA PET/CT and pelvic MRI within three months of each other at the University of California, Los Angeles with available imaging and follow-up data were included in our retrospective analysis. Two board-certified nuclear medicine physicians blinded to clinical information interpreted the PSMA PET/CT scans independently and described up to three positive findings. A third nuclear medicine physician resolved any disagreements (2:1 majority rule). In a similar framework, two radiologists interpreted the pelvic MRIs with a third radiologist serving as a tiebreaker. For patients with metastatic disease, PSMA PET/CT scans were interpreted according to PROMISE criteria. Data on disagreements between clinical PSMA PET/CT and pelvic MRI reads, disagreements between blinded and clinical PSMA PET/CT and pelvic MRI reads, and subsequent management based on findings from clinical PSMA PET/CT and pelvic MRI were collected. Results: 101 patients were included in this retrospective analysis, of which 84 (83%) had localized BCR and 17 (17%) had metastatic BCR. 10/84 (12%) patients with localized BCR had a negative clinical pelvic MRI and positive PSMA PET/CT, with 33% of these lesions noted to be in the lymph nodes, while 8/84 (10%) patients had a negative clinical PSMA PET/CT and positive pelvic MRI, with 100% of these lesions noted to be in the prostate or prostate bed. 12/17 (71%) patients with metastatic BCR had a positive clinical PSMA PET/CT and negative pelvic MRI. In 10/84 (12%) patients with localized BCR, the blinded PSMA PET/CT reads were negative while the clinical PSMA PET/CT reads were positive, and in 7/84 (8%) patients, the blinded pelvic MRI reads were negative while the clinical pelvic MRI reads were positive. In 2/17 (12%) patients with metastatic BCR, the blinded PSMA PET/CT reads were negative while the clinical PSMA PET/CT reads were positive, and in 1/17 (6%) patients, the blinded pelvic MRI reads were negative while the clinical pelvic MRI reads were positive. 48% of patients underwent radiation as a next step in management, 26% underwent biopsy, 15% underwent follow-up imaging, and 11% underwent other focal or systemic therapy. Conclusions: In this retrospective, descriptive analysis, there was good agreement between PSMA PET/CT and pelvic MRI for localized BCR, although pelvic MRI may overcall lesions in the prostate and prostate bed and miss nodal metastases. For patients with metastatic BCR, PSMA PET can disclose lesions that are outside the field-of-view of pelvic MRI.
Outcomes with first-line ipilimumab and nivolumab for patients with metastatic renal cell carcinoma by number of doses.
540 Background: Ipilimumab (IPI) and nivolumab (NIVO) are standard first-line systemic therapy for patients with metastatic renal cell carcinoma (RCC). The regimen is administered in combination once every 3 weeks for 4 doses, followed by NIVO maintenance. The dose and frequency of IPI appears to correlate with treatment safety and tolerability across cancer types. Further, studies in advanced melanoma have demonstrated that the efficacy of IPI + NIVO is largely driven by the first two doses in many patients (Postow MA et al., J Clin. Oncol. 2022). We assessed outcomes with IPI + NIVO by number of doses given in patients with metastatic RCC. Methods: We conducted a retrospective study of patients with metastatic RCC at Memorial Sloan Kettering Cancer Center treated with first-line IPI + NIVO. Baseline characteristics and treatment outcomes were obtained from electronic health record review. We calculated overall survival (OS) by the Kaplan-Meier method starting at 12 weeks after initiation of combination therapy, including all patients who were still alive and being followed at that time point and excluding those who had disease progression prior to completing 4 doses. We compared survival rates at 12 and 18 months and median OS for patients who received 4 doses versus those who received fewer than 4 doses. Results: Patients with metastatic RCC treated with first-line IPI + NIVO were included (N=222); 77% were male, 85% had clear cell RCC, 48% had sarcomatoid and/or rhabdoid features, and 87% had IMDC intermediate or poor risk disease. Regarding IPI + NIVO, 145 patients (65%) received all 4 doses, 30 (14%) received 3 doses, 21 (9%) received 2 doses, and 26 (12%) received 1 dose. The most common reasons for not completing all 4 doses (77, 35%) were toxicity (57%) and disease progression (21%). All 145 patients who received 4 doses and 44 who received fewer than 4 doses for reasons other than early progression or death were included in the analysis. OS in the 4 dose and <4 dose group at 18 months was 83% (95% CI: 76%, 89%) and 79% (95% CI: 63%, 88%), respectively. Conclusions: In this observational analysis, we found comparable OS rates in those patients who received all 4 doses of IPI + NIVO compared to those who received fewer than 4 doses for reasons other than disease progression, primarily toxicity. Four Doses of IPI + NIVO (N=145) Fewer Than Four Doses of IPI + NIVO, Excluding Early Disease Progression (N=44) 12-month OS (95% CI) 89% (82%, 93%) 86% (72%, 94%) 18-month OS (95% CI) 83% (76%, 89%) 79% (63%, 88%) Median OS, months (95% CI) 67.1 (40.1, NR) 82.5 (27.1, 109.3) Log-rank p value = 0.595
Mass cytometry-based deep immune cell profiling of metastatic clear cell renal cell carcinoma patients refractory to combined immune checkpoint and tyrosine kinase inhibitor therapy.
576 Background: Combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) improved outcomes for patients with metastatic clear cell renal cell carcinoma (mccRCC). However, some patients experience rapid disease progression. Identifying specific immune phenotypes and predictive circulating biomarkers is essential for the early detection of patients who may be refractory to ICI-TKI therapy. Methods: Serum samples and peripheral blood mononuclear cells (PBMCs) were collected from patients classified as complete responders (CR, n=4), partial responders (PR, n=10), and non-responders (NR, n=8) after 15 days (T1) and 1 month (T2) of nivolumab (ICI) and cabozantinib (TKI) therapy. Serum cytokines were analyzed using LEGENDplex, while PBMC immunophenotyping was performed using CyTOF to assess 37 immune cell populations and T cell markers related to activation, migration, and exhaustion. Results: In both responding and non-responding patients a common significant 90% reduction of PD1+TM3-CD8+ cells (p=0.0096 and p=0.0001, in CR and NR, respectively) and dendritic cells (decrease of 47% p=0.0004 in CR, 70% p=0.0059 in PR and 62% decrease p=0.0396 in NR) following therapy was observed. PD1+ Treg cells decreased significantly (93% decrease, p=0.0068) only in the CR after therapy. Additionally, CRs exhibited higher levels of exhausted PD1+ Treg cells (2.88 fold, p=0.0084) at baseline and an increased number of pro-inflammatory CD4+ Th2 cells (2 fold, p=0.0170) after one month compared to the other groups. PRs and NRs showed lower levels of natural killer cells (2.2 fold, p=0.0069), and a significant decrease of monocytes populations after therapy (45% decrease p=0.0008 in PRs, 40% decrease p=0.0012 in NRs). The CRs exhibited elevated levels of IL-23 (18 fold higher vs. NRs and 3 fold higher vs. PRs, p= 0.0094; p=0.0011) and IL-27 at baseline , and higher IL-15 and IL-18 levels post-therapy compared to the PR and NR. Kaplan-Meier plot analysis indicated that higher IL-23 levels correlated with an improved probability of PFS in all cancer patients treated with nivolumab (2.97 vs. 29.7 months in low vs. high expression cohorts; HR= 0.53 [95% CI 0.33 - 0.85], log-rank P = 0.0074). Conclusions: Our results suggest that patient’s initial immune profile might be significant predictor of treatment success and the likelihood of developing resistance.
Pathological subclassification of T3 upper tract urothelial carcinoma: Complementary evidence for existing guidelines.
841 Background: According to the current guidelines, upper tract urothelial carcinoma (UTUC), which encroaches beyond the muscularis propria but does not invade peripheral organs or perirenal fat, is classified as pathological T3 (pT3). However, the current classification definition of pT3 fails to meet clinical needs due to the significant heterogeneity of pT3 UTUC in terms of biological features and oncological outcomes. Therefore, the aim of this study was to explore the effect of subclassifying pT3 UTUC on oncological outcomes based on a large UTUC cohort from Southwest China. Methods: Data of pathologically confirmed UTUC patients treated with radical nephroureterectomy (RNU) treatment at West China Hospital of Sichuan University from May 2003 to June 2019 were retrospectively collected. Only patients with a diagnosis of initial pT3 and complete follow-up information were included in the study. pT3 was subclassified into pT3a (defined as tumor invasion of the ureteral adventitia or renal parenchyma) and pT3b (defined as tumor invasion of the ureter or peri-pelvic fat). The primary endpoints included cancer-specific survival (CSS), overall survival (OS) and recurrence-free survival (RFS). Results: A total of 326 patients with initial pT3 UTUC were finally included. According to our proposed subclassification, 232 cases were in pT3a group and 94 cases were in pT3b group. K-M analysis showed that the patients in pT3b group had significantly worse OS, CSS and RFS than those in pT3a group. Multifactorial Cox regression analysis demonstrated that patients in pT3b group had a 1.86-fold (95% CI, 1.19-2.91) risk of death, a 1.95-fold (95% CI, 1.21-3.17) risk of disease-related death and a 1.78-fold (95% CI, 1.21-3.17) risk of disease recurrence than those in the pT3a group. After adjustment for tumor size, tumor grade and lymph node metastasis the above findings remained statistically significant. Conclusions: Based on the presence or absence of invasion of the ureter and peri-pelvic fat, our study proposes a novel pT3 subclassification, which provide physicians with invaluable insight into better stratification of pT3 UTUC patients and provide a basis for individualized treatment.