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PURPOSE Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non–muscle-invasive downstaging to < pT2N0. RESULTS Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)–positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 ( P = .3 for association between PD-L1 and < pT2N0). CONCLUSION Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluation of tumor genomic evolution. We characterize changes in tumor fraction (TFx), somatic copy number alterations (SCNAs), and somatic mutations over time in patients (pts) with and without BRCA1/2 mutations and metastatic breast cancer (mBC) who received a PARP inhibitor (PARPi) or platinum chemotherapy. Specifically, we seek to identify the frequency of BRCA1/2 reversion mutations. Methods: Pts with mBC and germline or somatic BRCA1/2 mutations were identified on a banking protocol of prospectively-collected serial samples of blood and plasma. Control pts without a BRCA1/2 mutation were matched 2:1 by age and hormone receptor (HR) status. Ultra-low-pass whole genome sequencing (ULPWGS) with 0.1x depth was performed on all plasma samples (n=103) and the ichorCNA algorithm was used to determine TFx and SCNAs. Targeted panel sequencing (TPS) of 402 cancer-related genes was performed at 10,000x depth on plasma samples, and one blood sample per pt. The panel includes BRCA1/2 and 38 other DNA damage repair (DDR) genes. Somatic mutations were identified by joint calling with Mutect2 across plasma timepoints with paired pt normal blood. Germline variant calling from TPS on blood with HaplotypeCaller was used to confirm germline mutations in BRCA1/2. Results: We identified 10 pts with mBC with a germline (n=7) or somatic (n=3) BRCA1 (n=2) or BRCA2 (n=8) mutation and banked blood and plasma samples at 2-9 timepoints at a median of 8 weeks apart (range 1-43). The control cohort of 20 pts with mBC and wildtype BRCA1/2 was well matched by age and HR status. All pts with BRCA1/2 mutations received a PARPi and/or platinum chemotherapy at some point during sample collection. Half of control pts received platinum chemotherapy. Germline BRCA1/2 mutations were confirmed in all 7 pts with known germline mutations. Somatic BRCA2 mutations were confirmed in ctDNA in 2 of 3 patients. Among all samples, median TFx was 0.05 (range 0-0.80) with 35% of samples having TFx >0.10. There was no significant difference in TFx by age, receptor status, or active treatment with a PARPi or platinum. There was no significant change in the percent of genome with a SCNA over time. A reversion mutation of a germline BRCA2 mutation, restoring the open reading frame of BRCA2, was discovered at the last timepoint from 1 pt while receiving carboplatin. She had radiographic progression 4 weeks later. A germline BRCA1/2 reversion mutation in this cohort occurred in 2.3% of samples, 14.3% of pts. The somatic mutation landscape and clonal evolution of TPS using PyClone will be presented. Clonal evolution can show emerging and responding clusters of variants. For pts with available tissue specimens, somatic variants in ctDNA will be compared to somatic mutations detected in tissue with TPS. Conclusions: Evaluation of serial ctDNA samples for TFx, SCNAs, and somatic mutations from banked plasma and blood from pts with mBC is feasible. SCNAs were stable over time. The frequency of reversion mutations in BRCA1/2 was low, suggesting that either their incidence is low or ctDNA TPS is not sensitive enough to detect them. Citation Format: Katharine A Collier, David Tallman, Zachary T. Weber, Marcy Haynam, Elizabeth J. Adams, Janet Jenison, Sarah Asad, Maryam Lustberg, Mathew Cherian, Bhuvaneswari Ramaswamy, Sagar Sardesai, Nicole Williams, Robert Wesolowski, Jeffrey Vandeusen, Margaret E. Gatti-Mays, Ashley Pariser, Amir Mortazavi, Daniel G. Stover. Serial circulating tumor DNA from patients with metastatic breast cancer with and without BRCA1/2 mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-09.

Purpose: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). Patients and Methods: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. Results: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7–33.5], median PFS was 3.6 months (95% CI, 2.1–5.5), and median OS was 10.4 months (95% CI, 5.8–19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. Conclusions: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

Supplementary Data

Purpose:This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines.Patients and Methods:The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.Results:Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.Conclusions:The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

Supplementary Data from Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy

Purpose:This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI).Patients and Methods:A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability.Results:Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7–33.5], median PFS was 3.6 months (95% CI, 2.1–5.5), and median OS was 10.4 months (95% CI, 5.8–19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS.Conclusions:CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.

This file contains supplemental materials, tables, and figures.

Purpose:Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.Experimental Design:Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.Results:From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months; P < 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category.Conclusions:Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low �4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.

Background and Objectives REC-2282 is a novel histone deacetylase inhibitor that has shown antitumor activity in in vitro and in vivo models of malignancy. The aims of this study were to characterize the population pharmacokinetics of REC-2282 (AR-42) from the first-in-human (NCT01129193) and phase I acute myeloid leukemia trials (NCT01798901) and to evaluate potential sources of variability. Additionally, we sought to understand alternate body size descriptors as sources of inter-individual variability (IIV), which was significant for dose-normalized maximum observed concentration and area under the concentration-time curve (AUC). Methods Datasets from two clinical trials were combined, and population pharmacokinetic analysis was performed using NONMEM and R softwares; patient demographics were tested as covariates. Results A successful population pharmacokinetic model was constructed. The pharmacokinetics of REC-2282 were best described by a two-compartment model with one transit compartment for absorption, first-order elimination and a proportional error model. Fat-free mass (FFM) was retained as a single covariate on clearance (CL), though it explained < 3% of the observed variability on CL. Tumor type and formulation were retained as covariates on lag time, and a majority of variability, attributed to absorption, remained unexplained. Computed tomography (CT)-derived lean body weight estimates were lower than estimated lean body weight and fat-free mass measures in most patients. Analysis of dose-normalized AUC vs. body size descriptors suggests flat dosing is most appropriate for REC-2282. Conclusions FFM was identified as a significant covariate on CL; however, it explained only a very small portion of the IIV; major factors contributing significantly to REC-2282 pharmacokinetic variability remain unidentified. Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00722-z.

Objectives Two pilot studies of AR‐42, a pan‐histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra‐tumoral pharmacokinetics (PK) and pharmacodynamics (PD). Methods Pilot 1 is a subset analysis of a phase 1 study of AR‐42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment‐related adverse events (TRAEs) are reported (NCT01129193). Pilot 2 is a phase 0 surgical study of AR‐42 assessing intra‐tumoral PK and PD. AR‐42 was administered for 3 weeks pre‐operatively. Plasma and tumor drug concentrations and p‐AKT expression were measured (NCT02282917). Results Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR‐42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p‐AKT decreased in three of four VS. All tumors had higher AR‐42 concentrations than plasma. Conclusions AR‐42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40‐mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well‐tolerated and effective dose. A phase 2 study of AR‐42 for NF2‐associated tumors appears warranted. Level of Evidence 1b, 4.

Exercise and dietary (EX+D) interventions could represent an optimal treatment for attenuating or reversing adverse effects of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients. The Individualized Diet and Exercise Adherence-Pilot (IDEA-P) trial compared the effects of an EX+D intervention relative to standard-of-care (SC) treatment among PCa patients undergoing ADT. The present study evaluated the effects of the EX+D intervention on body composition (BC) obtained via dual-energy X-ray absorptiometry (DXA) in a subsample of IDEA-P patients. A secondary objective was to explore the association of adiposity and lean mass with mobility performance and strength.Complete DXA data were acquired from a subsample of 22 PCa patients (EX+D:Intention-to-treat analysis revealed EX+D resulted in significant improvements in fat mass (Findings suggest the EX+D intervention resulted in superior preservation of lean tissue and improvement in adiposity relative to SC treatment. Results underscore the utility of implementing EX+D interventions for preserving muscle mass and reducing adiposity in PCa patients undergoing ADT.

Purpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. Results: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months; P < 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.

Objectives Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown. Methods We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment. Results Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003). Conclusions Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.

Background In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616). Methods Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1). Results Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related. Conclusions Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing. Lay summary Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.

PURPOSE We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti‐PD‐1/PD‐L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti‐PD‐1/PD‐L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum‐based chemotherapy. DDR alterations (including ATM) were associated with a non‐significantly higher ORR to PD‐1/PD‐L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non‐significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations were associated with a non‐significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD‐1/PD‐L1 blockade versus 24% ORR in patients with, DDR alterations are associated with higher ORR and nonsignificantly prolonged OS in patients with advanced UC receiving PD‐1/PD‐L1 inhibitors. However, presence of ATM alterations correlated with shorter OS, irrespective of a nonsignificant trend towards higher ORR to anti‐PD‐1/PD‐L1 agents.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Cytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy.To evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy.A multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality.The study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2-79.8) compared to the ST alone group (19.1 months IQR 12.8-23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS.CN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.

467 Background: Neuroendocrine, small cell, or large cell carcinoma originating from the urothelium (uro-NE/SCC/LCC) is rare. Outcomes for metastatic disease are dismal. Treatment is extrapolated from small cell lung cancer, for which immune checkpoint inhibitors (ICIs) have modest activity. Preliminary activity has been reported with ICI for uro-NE. We aimed to compare real-world progression-free survival (PFS) and overall survival (OS) between ICI-containing and non-ICI-containing regimens in the first line (1L) metastatic setting for uro-NE/SCC/LCC. Methods: We performed a retrospective study at 11 cancer centers. Patients (pts) who received systemic therapy (2011-2021) for biopsy confirmed metastatic uro-NE/SCC/LCC were included. Pts with metastasis within 6 months of (neo)adjuvant chemotherapy (CT) (n=16) were excluded from 1L analyses. Results: 102 pts with metastatic uro-NE/SCC/LCC were evaluable. 17 (16.7%) had NE histology, 81 (79.4%) SCC, and 4 (3.9%) LCC. NE/SCC/LCC was mixed with urothelial histology in 19 (18.6%). Primary tumors were most often in the bladder (84.3%, n=86), less frequently upper tract (11.8%, n=12) or urethra (3.9%, n=4). 42 pts (41.2%) were previously treated for localized disease, the rest were de novo metastatic (n=60, 58.8%). Pts who received an ICI in any line (n=61) had significantly longer OS (p=0.038) than pts that never received an ICI (n=41). As shown in the table, in the 1L, ICI-containing regimens (n=33) resulted in significantly longer PFS, but not OS or ORR compared to non-ICI regimens (n=53). Subdividing 1L regimens into ICI without CT (n=14), CT without ICI (n=53), or ICI + CT (n=19), both PFS and OS were significantly different with similar ORR. ICI w/o CT had the longest median PFS and OS with an ORR 57.1% comparable to CT regimens. Of 61 pts that received ICI in any line, 14 (23.0%) had an immune-related adverse event of any grade; 11 (18.0%) received steroids. Conclusions: This is the largest ever report of ICI for metastatic uro-NE/SCC/LCC. ICIs were associated with improved outcomes with expected added toxicity. Further prospective investigation of ICI regimens is warranted. [Table: see text]

713 Background: The FOLH1 gene encodes prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein that is highly expressed in prostate cancer cells and on endothelial cells in the neovasculature of solid tumors, including RCC. PSMA has been used as a target for diagnostic imaging and therapeutic radioligand therapy. We utilized a database of molecularly profiled RCC tumors to evaluate associations with FOLH1 expression. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed for RCC patient specimens (n=1765) through Caris Life Sciences (Phoenix, AZ). FOLH1-High/Low expression were defined as ≥75th/

521 Background: Sacituzumab govitecan (SG) demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months (Mo) in metastatic urothelial carcinoma (mUC) patients (pts) progressing after platinum-based chemotherapy and PD1/L1 inhibitor, which led to accelerated US FDA approval in this setting. The combination of SG and pembrolizumab is safe and active following platinum-based chemotherapy. Nivolumab (NIVO) 1mg/kg plus Ipilimumab (IPI) 3mg/kg has shown promising activity in post-platinum mUC pts. Given the potential synergism between immunogenic cell death induced by SG and IPI-NIVO, we hypothesized that the combination of SG and IPI-NIVO would be safe and active as a frontline treatment for cisplatin ineligible mUC. Methods: 3+ 3 design was used for the phase I dose escalation of SG at 8 mg/kg and 10 mg/kg dose levels. IPI and NIVO were given at 3mg/kg and1mg/kg (I3+N1) intravenously (IV) every 3 weeks x 4 cycles followed by NIVO 360 mg IV day 1 every 3 weeks. SG was given IV at days 1,8 every 3 weeks The primary endpoint was safety and recommended phase 2 dose (RP2D) based on dose limiting toxicity (DLTs) observed in cycle 1; key secondary endpoints include ORR, DOR, PFS and OS. Key inclusion criteria were ECOG-PS 0-1, cisplatin-ineligibility, treatment naïve, no prior PD1/L1 inhibitor except >3 months earlier for non-metastatic disease. Results: The study has completed the phase I dose escalation after enrolling a total of 9 patients (8 men, 1-woman, median age: 74 years). 6 patients were enrolled at SG 8 mg/kg with 1 DLT, and 3 patients at 10 mg/kg with 2 DLTs. DLTs included grade 3 skin rash (n=2) and grade 3 pneumonitis (n=1). The RP2D of SG was determined to be 8 mg/kg with I3+N1. The most common treatment related adverse events (TRAE) included anemia (66.6%) neutropenia (66.6%), pruritus (66.6%), fatigue (66.6%), diarrhea (66.6%) and lymphopenia (55.5%). 2 patients developed grade 2 infusion reactions to SG. Other grade ≥ 3 TRAE included neutropenia (55.5%), anemia (33.3%), arthralgia (11.1%), and elevated amylase/lipase (11.1%). Both grade 2 pneumonitis and myositis were seen in 1 patient. Of the 9 pts, 6 pts (4 pts at SG dose of 8mg/kg and 2 pts at 10 mg/kg) were considered evaluable for response of whom 4 responded (ORR 66.6%) with 1 complete response and 3 partial responses. Median DOR was 9.2 Mo (range 4.6-12.0); mPFS was 8.8 Mo (95% CI 3.8-NR) and mOS was not reached. Conclusions: The RP2D of SG was identified as 8mg/kg in combination with Ipilimumab 3 mg/kg+ Nivolumab 1 mg/kg as first-line therapy for cisplatin-ineligible mUC. Early signals of promising activity were observed in a small cohort of evaluable pts. The Phase 2 trial is ongoing coupled with exploratory biomarker analyses. Clinical trial information: NCT04863885 .

650 Background: Management of metastatic renal cell carcinoma (mRCC) is highly individualized and often involves cytoreductive nephrectomy (CN) and systemic therapy (ST). The optimal sequencing of CN and ST is uncertain. A difference in perioperative outcomes based on sequence of CN and ST could influence decision-making. We conducted this NSQIP analysis to assess whether preoperative systemic therapy adversely impacted perioperative outcomes in patients receiving deferred CN. Methods: This analysis was conducted using the American College of Surgeons NSQIP Participant Use Data File for years 2019 and 2020. These years were selected because data on receipt of preoperative therapy is only available since 2019. Inclusion criteria were i) CPT code consistent with nephrectomy, ii) urologist operating surgeon & iii) presence of disseminated cancer. All cases with ICD-10 diagnosis codes not consistent with mRCC were excluded. Groups were stratified by their receipt of preoperative systemic therapy within 90 days before CN and we assessed 46 preoperative and perioperative outcomes. Results: The study cohort included 505 patients with 115 (23%) who received preoperative ST. No differences were noted in perioperative outcomes (Table). Patients receiving preoperative ST were more likely to be on steroids (23% vs. 7%, p0.05). Conclusions: Because preoperative ST did not have an appreciable impact on deferred CN perioperative outcomes, decision making for ST and CN sequencing should not be influenced by perioperative outcomes. Those who undergo deferred CN are unlikely to experience delayed time to surgery or perioperative complications from their ST. [Table: see text]

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

PURPOSE Patients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program–sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population. METHODS Patients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m2 intravenously followed by eribulin 1.4 mg/m2, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%. RESULTS Between June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each). CONCLUSION Gemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.

Purpose We evaluated the prognostic value of 18F-sodium fluoride (NaF) PET/CT in patients with urological malignancies treated with cabozantinib and nivolumab with or without ipilimumab. Methods We prospectively recruited patients with advanced urological malignancies into a phase I trial of cabozantinib plus nivolumab with or without ipilimumab. NaF PET/CT scans were performed pre- and 8 weeks post-treatment. We measured the total volume of fluoride avid bone (FTV) using a standardized uptake value (SUV) threshold of 10. We used Kaplan-Meier analysis to predict the overall survival (OS) of patients in terms of SUVmax, FTV, total lesion fluoride (TLF) uptake at baseline and 8 weeks post-treatment, and percent change in FTV and TLF. Result Of 111 patients who underwent NaF PET/CT, 30 had bone metastases at baseline. Four of the 30 patients survived for the duration of the study period. OS ranged from 0.23 to 34 months (m) (median 6.0 m). The baseline FTV of all 30 patients ranged from 9.6 to 1570 ml (median 439 ml). The FTV 8 weeks post-treatment was 56–6296 ml (median 448 ml) from 19 available patients. Patients with higher TLF at baseline had shorter OS than patients with lower TLF (3.4 vs 14 m; p = 0.022). Patients with higher SUVmax at follow-up had shorter OS than patients with lower SUVmax (5.6 vs 24 m; p = 0.010). However, FTV and TLF 8 weeks post-treatment did not show a significant difference between groups (5.6 vs 17 m; p = 0.49), and the percent changes in FTV (12 vs 14 m; p = 0.49) and TLF (5.6 vs 17 m; p = 0.54) also were not significant. Conclusion Higher TLF at baseline and higher SUVmax at follow-up NaF PET/CT corresponded with shorter survival in patients with bone metastases from urological malignancies who underwent treatment. NaF PET/CT may be a useful predictor of OS in this population.

Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

INTRODUCTION AND OBJECTIVE:The role of CN in the treatment of mRCC has been questioned with the recent approval of novel systemic therapy (ST) agents and the results of the CARMENA trial. Our objec...