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Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.

Includes: Table 1S. Baseline patient and disease characteristics. Table 2S. Tumor mutation burden status. Table 3S. PDL1 expression data. Figure 1S. Overall survival for the total cohort.

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Purpose: This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases.Patients and Methods: Fifteen treatment-naïve patients (n = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed.Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time.Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. Clin Cancer Res; 24(17); 4081–8. ©2018 AACR.

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Purpose:Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.Patients and Methods:Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints.Results:Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8–21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean Cmaxss of 104 ± 45 ng/mL and AUCτss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss, 315 ng/mL and AUCτss, 3,817 ng•h/mL).Conclusions:Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

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Purpose:Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.Patients and Methods:This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.Results:All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.Conclusions:Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

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PURPOSE In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473 ). METHODS We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B). RESULTS Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed. CONCLUSION In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings.Two hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed.Higher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4-3.6, p = .001; binary9.3: HR 1.7, 95% CI: 1.2-2.4, p = .007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6-3.3, p .001; binary: HR 1.8, 95% CI: 1.3-2.5, p .001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p = .007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99-1.9, p = .057).In the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.

Background Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1–based ICBs. Methods We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated. Results Eighty-six patients were included in the analysis; the median age was 63 years (range 33–84) and the median number of prior therapies was 2 (range 1–10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26–47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3–8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41–66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%). Conclusions Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.

Objective: Compare FDG-PET/CT, CT, and bone scan for detecting and monitoring bone metastases’ response in metastatic renal cell cancer (mRCC). Methods: Patients with mRCC prospectively underwent FDG-PET/CT, CT, and bone scans at baseline and after 8 weeks of therapy. Tumor visibility and metabolic activity were retrospectively recorded. Response was evaluated by PERCIST, RECIST, and MD Anderson bone criteria. Kaplan-Meier methodology estimated event-time distributions for PFS, OS, and time to symptomatic skeletal event (SSE). Log-rank test tested differences in event-time distributions between response at 8 weeks by response criteria. Results: Sixteen patients (n = 30; 53%) were evaluable. Baseline FDG-PET/CT detected more osseous metastases (n = 55) than CT (n = 45) or bone scan (n = 34). From baseline to 8 weeks, metabolic activity of lesions decreased >20%, while qualitative and quantitative CT and bone scan parameters were unchanged for most patients. Partial metabolic responders by PERCIST had longer PFS and OS (n = 5, 20+ months) versus those with stable (n = 9; PFS = 9.2 mos, OS = 8.7 mos) and progressive (n = 2; PFS = 5.4 mos, OS = 12.1 mos) metabolic disease, p = 0.09 and 0.42, respectively. By RECIST, longer PFS and OS was seen for stable (n = 12, PFS = 8.3 mos, OS = 17.7 mos) versus progressive (n = 4; PFS = 3.7 mos, OS = 7.5 mos) disease, p = 0.16, 0.02, respectively. OS was not reached, but estimated ≥20 mos, for 4 patients with RECIST SD and PERCIST PMR, compared to OS of 17.7 mos for other patients with RECIST SD. Conclusions: FDG-PET/CT identified more bone metastases and greater numbers of quantitative and qualitative treatment responses in mRCC compared to CT and bone scan. FDG-PET/CT also may identify a sub-group of patients with better outcomes than predicted by standard imaging modalities.

Background In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC. Methods Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology. Results Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01–1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01–0.43) and single-nucleotide variant (SNV) count Conclusions This three-factor model includes genomic (SNV count >9) and clinical (NLR

Cytoreductive nephrectomy (CN) was established as the standard of care for the management of metastatic renal cell carcinoma (mRCC) in the early 2000s. Since that time, systemic therapeutic options for mRCC have rapidly expanded and progressed. The CARMENA trial was a phase III prospective, randomized clinical trial that accrued patient from 2009 to 2017, and the results show that treatment with sunitinib is noninferior to treatment with CN followed by sunitinib. Because the findings of CARMENA suggest that systemic therapy should be considered alongside CN as frontline therapy for mRCC, it is therefore important to define the clear indications for CN in the management of mRCC which include palliation, nonclear cell histology, consolidative therapy after systemic therapy, and oligometastic disease. Furthermore, CN may become increasingly important as immunotherapeutic options become widely adopted in the future. Given the heterogeneous nature of mRCC, a multidisciplinary approach should be taken to tailor the use of systemic therapy and CN for each individual patient.

BACKGROUND Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P

Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)—an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis—in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. Key Points Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology. Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment. Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.

Purpose: The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets. Experimental Design: Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC. Results: FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently. Conclusions: Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.

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.

Background Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer. Patients and Methods Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis. Results A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer. Conclusion Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.

SRF388 is a first-in-class, anti-IL-27 antibody developed to enhance immune responses within the tumor microenvironment. Preclinical studies have demonstrated that IL-27 pathway blockade can inhibit tumor growth in mouse models of liver cancer and lung cancer metastases. There is also evidence that IL-27 pathway inhibition is accompanied by activation of the innate and adaptive arms of the immune system. An ongoing Phase I trial has shown good tolerability at all dose levels tested and preliminary monotherapy antitumor activity with SRF388 (NCT04374877). Here, we describe the preclinical and clinical data used to select a RP2D and characterize cytokine and chemokine changes observed in patients after treatment with SRF388. To guide selection of the RP2D, the relationship between maximal effective dose (MaxED), pharmacokinetics (PK), and whole blood inhibition of IL-27-mediated phosphorylation of STAT1 by SRF388 was evaluated in a mouse model of liver cancer. The concentration of SRF388 associated with optimal antitumor activity was ~20-fold above the concentration needed for complete inhibition (> 90%) of whole blood phosphorylated STAT1 (pSTAT1). These PK and activity relationships were also defined in patients during the dose-escalation phase of the trial and integrated with safety and efficacy data to select a monotherapy RP2D. In patients, PK were linear, no dose-limiting toxicities were reported, complete pSTAT1 inhibition was achieved throughout the first cycle at 0.3 mg/kg, and 1 patient experienced a confirmed partial response per RECIST version 1.1 at a dose of 10 mg/kg. In the MaxED mouse model, the area under the concentration versus time curve (AUC) associated with significant antitumor activity was 1720 day*μg/mL. In patients, the corresponding target AUC was achieved clinically at 10 mg/kg after a single dose of SRF388. Changes in the concentration of several serum cytokines and chemokines were observed after SRF388 treatment including an increase in IL-27, a phenomenon described for other anti-cytokine antibodies due to altered clearance of the cytokine-antibody complex. Changes in a subset of other serum cytokines/chemokines correlated with a reduction in target lesion size. Taken together, these data support the selection of a monotherapy RP2D of 10 mg/kg intravenously every 4 weeks for SRF388. These data highlight how complementary strategies utilizing preclinical and clinical biomarker evaluations can be employed to establish a monotherapy RP2D and assess biological activity of a first-in-class anti-cytokine antibody, SRF388, for patients with cancer. Citation Format: Jonathan A. Hill, Kerry F. White, Matthew Rausch, Jou-Ku Chung, Amita Patnaik, Aung Naing, Daniel Morgensztern, Charlene M. Mantia, Nizar M. Tannir, Lon S. Smith, Beth Bowers, Alex Alika, Lauren C. Harshman, Benjamin H. Lee. Determination of a recommended Phase 2 dose (RP2D) for SRF388, a first-in-class IL-27-blocking antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1137.

2501 Background: The immunoregulatory cytokine IL-27 upregulates inhibitory immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines (eg, IFNγ, TNFα). SRF388 is a fully human IgG1 blocking antibody to IL-27 with potential to promote immune activation in the tumor microenvironment. A phase 1 study was conducted to establish the preliminary safety of SRF388 and to identify recommended phase 2 doses (RP2D) suitable for monotherapy and combination expansions (NCT04374877). Methods: The dose-escalation study (accelerated single patient followed by standard 3+3) enrolled patients (pts) with advanced treatment-refractory solid tumors. Upon RP2D selection, monotherapy and combination expansions opened for treatment-refractory clear cell renal cell cancer (ccRCC), hepatocellular cancer (HCC), and non-small cell lung cancer. SRF388 was administered IV every 4 weeks (wks) as monotherapy and every 3 wks with pembrolizumab. Tumor response was assessed by RECIST1.1. Results: The monotherapy dose-escalation enrolled 29 pts with doses ranging from 0.003 to 20 mg/kg. Median age was 64 years. Most pts were female (62%) with ECOG PS of 1 (72%). Approximately 80% had prior PD-(L)1 blockade, and 48% had ≥4 prior therapies. Treatment-related adverse events (TRAEs) occurred in 21%, and all were low grade. Fatigue was the only TRAE reported in ≥10% (n = 3). No dose-limiting toxicities (DLTs) or Grade ≥3 TRAEs were observed. Median time on study was 9 wks (range 0–59). One patient with highly treatment-refractory NSCLC experienced a confirmed partial response (PR) at 8 wks that was durable for 20 wks. Nine pts (31%) experienced disease stabilization at 8 wks, with 6 of 9 exhibiting durable disease control at 6 months. Of the 7 pts with ccRCC in the dose-escalation portion of the trial, 3 (43%) experienced durable disease control for ≥20 wks (range: 20-32). With doses up to 20 mg/kg, SRF388 PK remain linear with an estimated T1/2 of 10-12 days. PK characteristics and safety profile support dosing every 3 or 4 wks. Based on safety, tolerability, PK, peripheral pSTAT1 inhibition, and preliminary efficacy, 10 mg/kg was selected as the RP2D. Both the pembrolizumab safety cohort (n = 10) and Stage 1 of the ccRCC monotherapy expansion (n = 17) have fully enrolled. Of the 10 evaluable pts with ccRCC, 1 confirmed monotherapy PR has been reported, enabling Stage 2 initiation. Changes in several serum cytokines and chemokines were observed after SRF388 administration, including expected increase in circulating IL-27 levels. Conclusions: Results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Updated data, including safety and clinical outcomes as well as correlative biomarker analyses, will be presented. Clinical trial information: NCT04374877.

BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR;ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative(CS=0), CD73lowor CD73high(< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.

Purpose: Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC. Patients and Methods: Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints. Results: Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8–21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean Cmaxss of 104 ± 45 ng/mL and AUCτss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss, 315 ng/mL and AUCτss, 3,817 ng•h/mL). Conclusions: Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1–3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

Purpose FGFR3-TACC3 (fibroblast growth factor receptor 3–transforming acidic coiled coil-containing protein 3) fusions have recently been identified as driver mutations that lead to the activation of FGFR3 in bladder cancer and other tumor types and are associated with sensitivity to tyrosine kinase inhibitors. We examined the clinical and molecular characteristics of patients with FGFR3-TACC3 fusions and hypothesized that they are enriched in a subset of patients with bladder cancer. Materials and Methods We correlated somatic FGFR3-TACC3 fusions with clinical and molecular features in two cohorts of patients with bladder cancer. The first cohort consisted of the muscle-invasive bladder cancer (MIBC) data set (n = 412) from The Cancer Genome Atlas. The second cohort consisted of patients with MIBC or high-grade non-MIBC at the Dana-Farber Cancer Institute that had targeted capture sequencing of a selected panel of cancer genes (n = 356). All statistical tests were two sided. The clinical response of one patient with FGFR3-TACC3 bladder cancer to an FGFR3 inhibitor was investigated. Results Overall, 751 patients with high-grade bladder cancer without FGFR3-TACC3 fusions and 17 with FGFR3-TACC3 fusions were identified in the pooled analysis of the data sets from The Cancer Genome Atlas and the Dana-Farber Cancer Institute. FGFR3-TACC3 fusions were enriched in patients age ≤ 50 years versus age 51 to 65 years versus those older than 65 years (pooled, P = .002), and were observed in four (12%) of 33 patients age ≤ 50 years in the pooled analysis. Similarly, FGFR3-TACC3 fusions were significantly more common in Asians (13%) compared with African Americans (4%) and whites (2%; pooled, P < .001), as well as in never smokers (5.6%) compared with ever smokers (1.1%; pooled, P < .001). One patient with the fusion who was treated with an FGFR3 inhibitor achieved complete remission for 10 months. Conclusion Clinical testing to identify FGFR3 fusions should be prioritized for patients with bladder cancer who are younger, never smokers, and/or Asian.

BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC. METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods. RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion. CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Background Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. Methods Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). Results There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. Conclusions Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

Importance Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear. Objective To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. Design, Setting, and Participants This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy. Exposures Receipt of cabozantinib monotherapy at any line of treatment. Main Outcomes and Measures Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. Results Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. Conclusions and Relevance In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.

Background Overall survival (OS) is a critical endpoint in adjuvant trials but requires long durations to events and significant patient resources. In the current study, the authors assessed whether disease-free survival (DFS) can be an early clinical surrogate for OS in the adjuvant setting for localized renal cell carcinoma (RCC). Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the authors performed a systematic literature review of PubMed and the American Society of Clinical Oncology, European Society for Medical Oncology, and ClinicalTrial.gov Web sites (1996-2016). Inclusion in the current study required randomized controlled trials (RCTs) of adjuvant systemic therapy for localized RCC after nephrectomy with ≥3 years of outcomes data. Data regarding hazard ratios (HRs) and 5-year event-free rates from Kaplan-Meier estimates were extracted. A trial-level meta-analysis correlated estimates of 5-year DFS and 5-year OS as well as treatment effects (HRs) on these endpoints, weighted by the number of DFS events. R-squared ≥ 0.7 was prespecified as being indicative of a strong correlation and the potential for surrogacy. Results Thirteen RCTs encompassing 6473 patients who were treated with a variety of systemic therapies met eligibility. Only a modest correlation was observed between 5-year DFS and 5-year OS rates (R-squared, 0.48; 95% confidence interval, 0.14-0.67) and between treatment effects as measured by DFS and OS HRs (R-squared, 0.44; 95% confidence interval, 0.00-0.69). Conclusions Across RCTs of adjuvant systemic therapy for localized RCC, there was no strong correlation noted between 5-year DFS and 5-year OS rates or between treatment effects on these endpoints. These results highlight the need to identify alternative and more rapid clinical or biologic endpoints to hasten drug development and improve clinical outcomes. Cancer 2018;124:925-33. © 2017 American Cancer Society.

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0–300): intensity of c-Met staining (0–3) x % of positive cells (0–100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Given the lack of randomized evidence comparing trimodal therapy (TMT) to radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB), we performed an observational cohort study to examine the comparative effectiveness of these two definitive treatments. Within the National Cancer Data Base (2004-2011),we identified 1257 (9.8%) and 11 586 (90.2%) patients who received TMT and RC, respectively. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis showed that median overall survival (OS) was similar between the TMT (40 mo, 95% confidence interval [CI] 34-46) and RC groups (43 mo 95% CI 41-45; p=0.3). In IPTW-adjusted Cox regression analysis with a time-varying covariate, TMT was associated with a significant adverse impact on long-term OS (hazard ratio 1.37, 95% CI 1.16-1.59; p0.001). Interaction terms indicated that the adverse treatment effect of TMT versus RC decreased with age (p=0.004), while there was no significant interaction with gender (p=0.6), Charlson comorbidity index (p=0.09) or cT stage (p=0.8). In conclusion, we found that TMT was generally associated with worse long-term OS compared to RC for muscle-invasive UCB. However, the survival benefit of RC should be weighed against the risks of surgery, especially in older patients. These results are preliminary and emphasize the need for a randomized controlled trial to compare TMT versus RC.We examined the comparative effectiveness of trimodal therapy versus radical cystectomy for muscle-invasive urothelial carcinoma of the bladder. We found that trimodal therapy was generally associated with worse long-term overall survival, although there may be no difference with radical cystectomy in older individuals.

Introduction The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, “Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer,” was held in Carlsbad, California from June 14-17, 2017. Methods The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. Results The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. Discussion This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer.

Background Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO-mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy. Methods We queried two institutional clinical databases (Dana-Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan-Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors. Results Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57-1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69-1.16, P = 0.38) in the statin users versus non-users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57-1.10). Conclusions Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide- and docetaxel-naive JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.

Purpose: The use of large-field external beam reirradiation (re-RT) after pelvic radiation therapy (RT) for genitourinary (GU) cancers has not been reported. We report the results of such treatment in patients with either symptomatic GU second malignant neoplasms or locally recurrent pelvic tumors after initial RT for whom surgery or further systemic therapy was not an option. Methods and materials: The records of 28 consecutive patients with advanced, bulky GU malignancies treated with high-dose, large-field re-RT with palliative intent between 2008 and 2014 were retrospectively reviewed. Descriptive outcome analyses focused on toxicities and symptom control, and responses were evaluated by 2 independent observers. Results: Twenty-seven male patients (96%) were included. Median initial external beam RT dose was 64 Gy (range, 30-75.6 Gy). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At the time of re-RT, there were 16 local recurrences and 12 second malignant neoplasms together comprising 16 bladder, 10 prostate, 1 ureteral, and 1 penile cancer. Indications for re-RT were pain and bleeding/hemorrhage. The median equivalent sphere diameter planning target volume for re-RT was 8.6 cm (range, 4.7-16.3 cm). Given the severity of the symptoms and the bulk of the disease at the time of re-RT, a higher dose of RT was administered. The median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received

PURPOSE Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer. PATIENTS AND METHODS Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored. RESULTS Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP. CONCLUSION Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.

Background Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis. Objective To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents. Design, setting, and participants We analyzed two cohorts: an institutional cohort (n = 146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n = 4144) receiving interferon-α (n = 510), mammalian target of rapamycin (mTOR) inhibitors (n = 660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n = 2974) on phase II/III clinical trials. Outcomes measurements and statistical analysis The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors. Results and limitations Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n = 31, 21%) had a lower ORR (12.9% vs 34.8%, p = 0.026) and shorter PFS (adjusted hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.20–3.20, p = 0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n = 709, 17%) adversely impacted OS in patients treated with interferon (HR = 1.62, 95% CI 1.13–2.31, p = 0.008) or with VEGF-TT and prior cytokines (HR = 1.65, 95% CI 1.04–2.62, p = 0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration. Conclusions Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs. Patient summary We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use.

Adjuvant therapy for non-metastatic renal cell carcinoma (RCC) remains controversial. Of the four reported randomized controlled trials evaluating adjuvant vascular endothelial growth factor (VEGF) inhibition, only one met its primary endpoint. The S-TRAC study demonstrated a statistically significant improvement in disease-free survival (DFS) of greater than 1 year with adjuvant sunitinib compared to placebo in patients with high-risk localized RCC and earned it FDA approval. However, the larger ASSURE study which reported first did not find a difference in DFS or overall survival between 1 year of adjuvant sunitinib or sorafenib compared to placebo. Given the discordant results of the two sunitinib studies, two other negative studies of adjuvant targeted therapy with pazopanib and axitinib, the lack of definite overall survival benefit in any study, and the high incidence of treatment-related adverse events with sunitinib, we do not recommend the routine use of adjuvant sunitinib. The decision to offer adjuvant sunitinib should be considered on an individual basis after an informed discussion of the potential toxicities and the risk/benefit ratio. Despite numerous efforts and recently published works, there is a paucity of prognostic and predictive molecular biomarkers in RCC. Further investigation is needed to discover new tools that can enhance the identification of patients who are most likely to benefit from adjuvant treatment beyond pathologic stage. Immune checkpoint inhibitors have great potential to significantly improve outcomes in high-risk localized RCC. Building on their established efficacy in the metastatic setting, several ongoing clinical trials are evaluating their value as single agents or in combination in the neoadjuvant and adjuvant settings. At this time, we recommend participation in clinical trials as the preferred therapeutic option for patients with high-risk, non-metastatic RCC planned for nephrectomy.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

Background: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. Objective: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. Design, setting, and participants: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic. ±. RP) only, first-line platinum-based chemotherapy given. Intervention: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. Outcome measures and statistical analysis: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. Results and limitations: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p = 0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p = 0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. Conclusions: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. Patient summary: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies. In contemporary cohorts of patients with metastatic pelvic or retroperitoneal lymph nodes from bladder cancer, we found no survival benefit from postchemotherapy surgery versus observation in a retrospective study. Performing postchemotherapy lymphadenectomy remains investigational in patients with metastatic bladder cancer.

Background The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. Materials and Methods A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. Results Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1–38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7–93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8–17.6) and 49.3% (95% CI: 28.2–67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. Conclusion Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. Implications for Practice Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

98 Background: Treatment (tx) options for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) to bone are limited. Radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab (pem) are infrequent. As R223 may increase immunogenicity of mCRPC to bone and increase activity of CPI, we undertook a Phase 2 study to assess safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pem vs. R223 alone. Methods: Eligibility required mCRPC to bone with no visceral metastases (mets) or lymph nodes > 2 cm, ECOG PS 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI. Pts underwent bone bx at screening and at 8 wks. Pts were stratified by alkaline phosphatase ≥220 vs. < 220 U/L and high vs. low volume bony mets (CHAARTED criteria) and randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B). If restaging after 3 doses R223 showed at least stable disease, pts in Arm A continued pem alone until progressive disease (PD). Upon PD, R223 was resumed if no new visceral mets. Pts continued tx until clinical/radiologic PD, unacceptable toxicity or completion of 6 R223 doses. The primary endpoint was difference in CD4+ and CD8+ T-cell infiltrate in 8 wk vs. baseline bx; secondary endpoints were safety/tolerability, radiographic progression-free survival (rPFS) and OS. Exploratory endpoints included PSA response and rate of symptomatic skeletal events (SSEs). Results: Of 45 pts enrolled, 42 received study tx (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone bx. Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 wks was 0.90 (range 0.0-26.6) in Arm A and 0.40 (0.0-13.0) in Arm B (P = 0.87); for CD8+ cells, median 0.67 (0.0-40.4) in Arm A and 0.40 (0.1-28.8) in Arm B (P = 0.77). Grade 3 treatment-related non-hematologic adverse events (AEs) occurred in 3 pts (10%) in Arm A (pneumonitis, diarrhea, AST increased); none in Arm B. Median rPFS was 6.7 mo (95% CI 2.7-11.0 mo) in Arm A and 5.7 mo (2.6-NR) in Arm B. Median OS was 16.9 mo (12.7-NR) in Arm A and 16.0 mo (9.0-NR) in Arm B. 3 pts (10%) in Arm A and 0 in Arm B had PSA reduction of ≥ 50%. SSE rate was 38% in Arm A and 54% in Arm B, with pathologic fractures in 0% of pts in Arm A and 23% in Arm B. Conclusions: In the 62% of treated pts with evaluable paired bx at baseline and after 8 wks, there was no evidence of increased CD4+ or CD8+ T-cell infiltration with R223 + pem. Additional biomarker analyses will be presented. This study revealed that R233 + pem did not result in unexpected AEs, but did not lead to prolonged rPFS or OS compared to R223 alone to support this two-drug combination in a biomarker-unselected population in this setting. Clinical trial information: NCT03093428.

306 Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.

310 Background: Cabo shows robust clinical activity in mRCC. Patients (pts) with BM have been underrepresented in clinical trials and effective systemic therapy is lacking. We retrospectively characterized the clinical activity and toxicity of cabo in pts with BM from RCC. Methods: Consecutive medical records from mRCC pts with BM treated with cabo monotherapy across 15 institutions were reviewed. Pts were grouped by radiologic presence (cohort 1) or absence (cohort 2) of progressing intracranial metastases. Brain-directed local therapy was allowed but radiological confirmation of intracranial progression at cabo start was required in cohort 1. Radiological response rate was investigator-assessed by modified RECIST 1.1 for intracranial and RECIST 1.1 for extracranial responses. Time to treatment failure (TTF) and overall survival (OS) were estimated by Kaplan-Meier. Results: We identified 69 pts with BM from RCC, 25 (36%) in cohort 1 and 44 (64%) in cohort 2. Majority were IMDC intermediate/poor (87%) and received cabo as ≥2nd line (75%). Median time from mRCC diagnosis to BM was 19.1 months (mos) (IQR 4.4-39.5). Overall, median number of BM was 3 (range 1-27) and median size of largest lesion was 1.2 cm (range 0.2-6.6) with frontal (62%) and parietal (48%) as the most frequent localizations. Prior brain directed therapy was used in 65% and 93% of pts in cohort 1 and 2 respectively. Median follow-up after cabo initiation was 11 mos (range 4-72). Twenty three percent of pts remained on therapy while 52% discontinued for progression and 9% for toxicity. Intracranial response rate was 61% (95%CI 39%-80%), with 3 complete responses, for cohort 1 and 57% (95%CI 41%-72%) for cohort 2. Only 10% (n = 7) had intracranial progression as best response. For cohort 1, extracranial response was 52% (95%CI 31%-72%), median TTF was 9.9 mos (95%CI 5.9-14.0) and OS was 14.7 mos (95%CI 7.7-23.0). For cohort 2, extracranial response was 41% (95%CI 26%-57%), TTF was 9.0 mos (95%CI 4.6-11.4) and OS was 14.1 mos (95%CI 11.0-22.0). Most common adverse events were fatigue (77%) and diarrhea (46%). Eight pts received concomitant brain-directed treatment during cabo therapy without neurological toxicities. Conclusions: Cabo shows significant intracranial activity and acceptable safety profile in pts with BM from RCC. [Table: see text]