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Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711., (© 2024. The Author(s).)

Purpose: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression., Patients and Methods: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated., Results: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels., Conclusions: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels., (©2024 American Association for Cancer Research.)

What Is This Summary About?: Sacituzumab govitecan (brand name: TRODELVY ® ) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan., What Are the Key Takeaways?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan., What Were the Main Conclusions Reported by the Researchers?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious. Clinical Trial Registration : NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).

Background: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear., Patients and Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up., Results: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status., Conclusions: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 that depletes tumor-associated macrophages. In this study, the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC. Eligible patients had clear cell RCC with disease progression on prior CPI either in combination or sequentially with VEGF-TKI. Patients were treated with PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days. The primary objective was to assess safety and tolerability and secondary objectives included pharmacokinetics and anti-tumor activity by RECIST v1.1. Seventeen patients were enrolled with a median age of 67 years, 82% male, 100% had prior CPI, and 76% had received three or more prior lines of therapy. The combination of PY314 and pembrolizumab demonstrated an acceptable safety profile with 47.1% any grade treatment-related adverse events (AE) (including only 5.9% grade ≥ 3), the most common being fatigue, pyrexia, nausea, and infusion-related reactions. One patient achieved a partial response (6%), and four patients had stable disease (24%) as their best response. The median PFS was 1.4 months (95% CI 1.2- 3.8). The combination of PY314 and pembrolizumab was safe, but the limited anti-tumor effect observed suggests that TREM2 targeting in conjunction with PD-1 blockade may not overcome resistance to prior CPI. Further investigation is warranted to determine if improved efficacy can be achieved in IO-naïve settings. Trial Registration: NCT04691375., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer., Methods: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression., Results: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods., Conclusions: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: We have previously reported that a plasmid DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) had greater clinical activity when given in combination with pembrolizumab to patients with metastatic, castration-resistant prostate cancer. The current trial was conducted to evaluate vaccination with PD-1 blockade, using nivolumab, in patients with early, recurrent (M0) prostate cancer., Methods: Patients with M0 prostate cancer were treated with pTVG-HP (100 µg administered intradermally) and nivolumab (240 mg intravenous infusion) every 2 weeks for 3 months, and then every 4 weeks for 1 year of total treatment. Patients were then followed for an additional year off treatment. The primary objectives were safety and complete prostate-specific antigen (PSA) response (PSA<0.2 ng/mL)., Results: 19 patients were enrolled. No patients met the primary endpoint of complete PSA response; however, 4/19 (21%) patients had a PSA decline >50%. Median PSA doubling times were 5.9 months pretreatment, 25.6 months on-treatment (p=0.001), and 9.0 months in the subsequent year off-treatment. The overall median radiographic progression-free survival was not reached. Grade 3 or 4 events included adrenal insufficiency, fatigue, lymphopenia, and increased amylase/lipase. 9/19 (47%) patients developed immune-related adverse effects (irAE). The development of irAE and increased CXCL9 were associated with increased PSA doubling time. Quantitative NaF PET/CT imaging showed the resolution of subclinical lesions along with the development of new lesions at each time point., Conclusions: In this population, combining nivolumab with pTVG-HP vaccination was safe, and immunologically active, prolonged the time to disease progression, but did not eradicate disease. Quantitative imaging suggested that additional treatments targeting mechanisms of resistance may be required to eliminate tumors., Trial Registration Number: NCT03600350., Competing Interests: Competing interests: DGM has ownership interest, has received research support, and serves as consultant to Madison Vaccines, which has licensed material described in this manuscript and supported this trial. None of the other authors have relevant potential conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials., Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017-2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days., Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 < 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 < 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days., Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported., Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings., (©2023 American Association for Cancer Research.)

Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC)., Experimental Design: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines., Results: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo., Conclusions: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC., (©2023 The Authors; Published by the American Association for Cancer Research.)

Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Taylor, Kosoff, Emamekhoo, Lang and Kyriakopoulos.)

Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%-80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study., (©2023 American Association for Cancer Research.)

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.MethodsWe performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.ResultsUsing the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.ConclusionOur analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.FundingNIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation - PCF Challenge Award).

Purpose: Liquid biopsies in metastatic renal cell carcinoma (mRCC) provide a unique approach to understand the molecular basis of treatment response and resistance. This is particularly important in the context of immunotherapies, which target key immune-tumor interactions. Unlike metastatic tissue biopsies, serial real-time profiling of mRCC is feasible with our noninvasive circulating tumor cell (CTC) approach., Methods: We collected 457 longitudinal liquid biopsies from 104 patients with mRCC enrolled in one of two studies, either a prospective cohort or a phase II multicenter adaptive immunotherapy trial. Using a novel CTC capture and automated microscopy platform, we profiled CTC enumeration and expression of HLA I and programmed cell death-ligand 1 (PD-L1). Given their diametric immunological roles, we focused on the HLA I to PD-L1 ratio (HP ratio)., Results: Patients with radiographic responses showed significantly lower CTC abundances throughout treatment. Furthermore, patients whose CTC enumeration trajectory was in the highest quartile (> 0.12 CTCs/mL annually) had shorter overall survival (median 17.0 months v 21.1 months, P < .001). Throughout treatment, the HP ratio decreased in patients receiving immunotherapy but not in patients receiving tyrosine kinase inhibitors. Patients with an HP ratio trajectory in the highest quartile (≥ 0.0012 annually) displayed significantly shorter overall survival (median 18.4 months v 21.2 months, P = .003)., Conclusion: In the first large longitudinal CTC study in mRCC to date to our knowledge, we identified the prognostic importance of CTC enumeration and the change over time of both CTC enumeration and the HP ratio. These insights into changes in both tumor burden and the molecular profile of tumor cells in response to different treatments provide potential biomarkers to predict and monitor response to immunotherapy in mRCC.

Background: We previously reported a trial using a DNA vaccine encoding prostatic acid phosphatase (MVI-816, pTVG-HP), given over 12 weeks concurrently or sequentially with pembrolizumab, in patients with mCRPC. We report the final analysis of this trial following two additional treatment arms in which patients with mCRPC continued concurrent treatment until progression., Materials and Methods: Patients with mCRPC were treated with MVI-816 and pembrolizumab every 3 weeks (arm 3, n=20) or MVI-816 every 2 weeks and pembrolizumab every 4 weeks (arm 4, n=20). The primary objectives were safety, 6-month progression-free survival (PFS), median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations., Results: In 25 patients with measurable disease, there were no complete response and one confirmed partial response in a patient who subsequently found to have an MSI hi tumor. 4/40 patients (10%) had a prostate-specific antigen decline >50%. The estimated overall radiographic PFS rate at 6 months was 47.2% (44.4% arm 3, 61.5% arm 4). Accounting for all off-study events, overall median time on treatment was 5.6 months (95% CI: 5.4 to 10.8 months), 5.6 months for arm 3 and 8.1 months for arm 4 (p=0.64). Thirty-two per cent of patients remained on trial beyond 6 months without progression. Median overall survival was 22.9 (95% CI: 16.2 to 25.6) months. One grade 4 event (hyperglycemia) was observed. Immune-related adverse events (irAEs) >grade 1 were observed in 42% of patients overall. Interferon-γ and/or granzyme B immune response to prostatic acid phosphatase was detected in 2/20 patients in arm 3 and 6/20 patients in arm 4. Plasma cytokines associated with immune activation and CD8+ T-cell recruitment were augmented at weeks 6 and 12. The development of irAE was significantly associated with a prolonged time on treatment (HR=0.42, p=0.003). Baseline DNA homologous recombination repair mutations were not associated with longer time to progression., Conclusions: Findings here demonstrate that combining programmed cell death 1 blockade with MVI-816 is safe, can augment tumor-specific T cells, and can result in a favorable 6-month disease control rate. Correlative studies suggest T-cell activation by vaccination is critical to the mechanism of action of this combination. Future randomized clinical trials are needed to validate these findings., Trial Registration Number: NCT02499835., Competing Interests: Competing interests: DGM has ownership interest, has received research support, and serves as consultant to Madison Vaccines, which has licensed material described in this manuscript and supported this trial., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC)., Methods and Materials: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations., Results: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection., Conclusion: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2-directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC., Methods: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety., Results: Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events., Conclusion: SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population., Competing Interests: Scott TagawaConsulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, Abbvie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, Seattle Genetics, AIkido PharmaResearch Funding: Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, Clovis OncologyTravel, Accommodations, Expenses: Sanofi, Immunomedics, AmgenUncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics Arjun BalarHonoraria: Merck, Genentech/Roche, AstraZeneca/MedImmuneConsulting or Advisory Role: Immunomedics, Bristol Myers Squibb, Genentech/Roche, Merck, Cerulean Pharma, AstraZeneca/MedImmune, Pfizer/EMD Serono, Incyte, Seattle Genetics/Astellas, Nektar, Dragonfly Therapeutics, GlaxoSmithKlineResearch Funding: Immunomedics, Merck, Genentech/Roche, AstraZeneca/MedImmune, Seattle Genetics Daniel PetrylakStock and Other Ownership Interests: Bellicum Pharmaceuticals, TYMEConsulting or Advisory Role: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Lilly, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, Urogen pharma, Advanced Accelerator Applications, Ipsen, Bicycle Therapeutics, Mirati Therapeutics, Monopteros TherapeuticsResearch Funding: Progenics, Sanofi, Endocyte, Genentech, Merck, Astellas Medivation, Novartis, AstraZeneca, Bayer, Lilly, Innocrin Pharma, MedImmune, Pfizer, Roche, Seattle Genetics, Clovis Oncology, Bristol Myers Squibb, Advanced Accelerator Applications, Agensys, BioXCel therapeutics, Eisai, Mirati Therapeutics, ReplimuneExpert Testimony: Celgene, sanofi Arash RezazadehStock and Other Ownership Interests: ECOM MedicalConsulting or Advisory Role: Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, Bristol Myers Squibb, EMD Serono, Immunomedics, Gilead SciencesSpeakers' Bureau: Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, Bristol Myers Squibb, Amgen, Exelixis, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, Seattle Genetics/Astellas, Myovant Sciences, Gilead Sciences, AVEOResearch Funding: Genentech, Exelixis, Janssen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Macrogenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, EpizymeTravel, Accommodations, Expenses: Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, AstraZeneca Yohann LoriotHonoraria: Sanofi, PfizerConsulting or Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, MSD Oncology, Seattle Genetics, Bristol Myers Squibb, Immunomedics, Taiho PharmaceuticalResearch Funding: Sanofi, Janssen Oncology, MSD Oncology, AstraZeneca, Clovis Oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, NektarTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, Seattle Genetics Aude FlechonHonoraria: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Janssen-Cilag, Astellas Pharma, Pfizer, Sanofi/Aventis, Roche/Genentech, Bayer, Ipsen, AAA HealthCareTravel, Accommodations, Expenses: Astellas Pharma, Sanofi/Aventis, Janssen-Cilag, Bayer, Pfizer, Ipsen, Bristol Myers Squibb, AstraZeneca, MSD Oncology, Roche/Genentech, AAA HealthCare Rohit JainHonoraria: AlphasightsConsulting or Advisory Role: Taiho Oncology, Pfizer, Seattle Genetics/Astellas, Gilead Sciences, EMD SeronoSpeakers' Bureau: Seattle Genetics/Astellas Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Lilly, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas PharmaResearch Funding: Bayer, Bristol Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi Manojkumar BupathiHonoraria: Bristol Myers Squibb, Exelixis, AstraZeneca, Pfizer, Astellas PharmaConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, ExelixisSpeakers' Bureau: AstraZeneca, Bristol Myers Squibb, Pfizer, Exelixis, Astellas Pharma Philippe BarthelemyHonoraria: Ipsen, Bristol Myers Squibb, MSD, Astellas Pharma, Janssen-Cilag, Pfizer, Merck KGaAConsulting or Advisory Role: Ipsen, Bristol Myers Squibb, MSD Oncology, Pfizer, Janssen-Cilag, AstraZeneca, AmgenTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, MSD, Ipsen Phillip PalmbosResearch Funding: Roche, Immunomedics Christos KyriakopoulosConsulting or Advisory Role: Exelixis, Sanofi, AVEO, EMD Serono, Janssen OncologyResearch Funding: Sanofi Damien PouesselHonoraria: Ipsen, Janssen Oncology, Bristol Myers Squibb, AstraZeneca, Merck, Astellas PharmaConsulting or Advisory Role: Astellas Pharma, AstraZeneca, Janssen Oncology, Pfizer, SanofiResearch Funding: Incyte, Merck Sharp & Dohme, Roche, Bristol Myers Squibb, AstraZeneca, Janssen Oncology, Seattle GeneticsTravel, Accommodations, Expenses: Janssen Oncology, AstraZeneca, Pfizer Cora SternbergConsulting or Advisory Role: BMS, MSD, Pfizer, Roche-Genentech, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Sanofi-Genzyme, Immunomedics, now Gilead, Foundation Medicine, CCO Clinical, Janssen, NCIResearch Funding: Pfizer, MSD, Astellas, BMS, Immunomedics, now Gilead, Arvinas, Mirati Quan HongEmployment: Immunomedics, Gilead SciencesLeadership: ImmunomedicsStock and Other Ownership Interests: Immunomedics Trishna GoswamiEmployment: Immunomedics/GileadLeadership: Immunomedics/GileadStock and Other Ownership Interests: Immunomedics/GileadPatents, Royalties, Other Intellectual Property: Patents around combinations with TrodelvyTravel, Accommodations, Expenses: Immunomedics/Gilead Loretta ItriEmployment: Immunomedics/GileadLeadership: Immunomedics/GileadStock and Other Ownership Interests: ImmunomedicsConsulting or Advisory Role: ImmunomedicsTravel, Accommodations, Expenses: Immunomedics Petros GrivasConsulting or Advisory Role: Merck, Bristol Myers Squibb, AstraZeneca, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Pfizer, Janssen, Bayer, Genzyme, Mirati Therapeutics, Exelixis, Roche, GlaxoSmithKline, Genentech, Immunomedics, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLCResearch Funding: Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Bristol Myers Squibb, Debiopharm Group, Merck, QED Therapeutics, Kure It Cancer Research, GlaxoSmithKline, Mirati TherapeuticsNo other potential conflicts of interest were reported.

Background: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature., Methods: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ 2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival., Results: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST., Conclusions: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

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.

Purpose: Intrapatient treatment response heterogeneity is under-recognized. Quantitative total bone imaging (QTBI) using 18 F-NaF positron emission tomography/computed tomography (PET/CT) scans is a tool that allows characterization of interlesional treatment response heterogeneity in bone. Understanding spatial-temporal response is important to identify individuals who may benefit from treatment beyond progression., Patients and Methods: Men with progressive metastatic castration-resistant prostate cancer (mCRPC) with at least two lesions on bone scintigraphy were enrolled and treated with enzalutamide 160 mg daily (ClinicalTrials.gov identifier: NCT02384382). 18 F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of prostate-specific antigen (PSA) progression, standard radiographic or clinical progression, or at 2 years without progression (PET3). QTBI was used to determine lesion-level response. The primary end point was the proportion of men with at least one responding bone lesion on PET3 using QTBI., Results: Twenty-three men were enrolled. Duration on treatment ranged from 1.4 to 34.1 months. In general, global standardized uptake value (SUV) metrics decreased while on enzalutamide (PET2) and increased at the time of progression (PET3). The most robust predictor of PSA progression was change in SUV hetero (PET1 to PET3; hazard ratio, 3.88; 95% CI, 1.24 to 12.1). Although overall functional disease burden improved during enzalutamide treatment, an increase in total burden (SUV total ) was seen at the time of progression, as measured by 18 F-NaF PET/CT. All (22/22) evaluable men had at least one responding bone lesion at PET3 using QTBI., Conclusion: We found that the proportion of progressing lesions was low, indicating that a substantial number of lesions appear to continue to benefit from enzalutamide beyond progression. Selective targeting of nonresponding lesions may be a reasonable approach to extend benefit.

Purpose: Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8 + T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial., Patients and Methods: Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen deprivation therapy were randomly assigned to receive pTVG-AR on one of two treatment schedules over one year, and with or without GM-CSF as a vaccine adjuvant. Patients were followed for 18 months. Primary objectives were safety and immune response. Secondary objectives included median time to PSA progression, and 18-month PSA-PFS (PPFS)., Results: Forty patients were enrolled at three centers. Twenty-seven patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event before the 18-month time point. No grade 3 or 4 adverse events were observed. Of 30 patients with samples available for immune analysis, 14 (47%) developed Th1-type immunity to the AR LBD, as determined by IFNγ and/or granzyme B ELISPOT. Persistent IFNγ immune responses were observed irrespective of GM-CSF adjuvant. Patients who developed T-cell immunity had a significantly prolonged PPFS compared with patients without immunity (HR = 0.01; 95% CI, 0.0-0.21; P = 0.003)., Conclusions: pTVG-AR was safe and immunologically active in patients with mCSPC. Association between immunity and PPFS suggests that treatment may delay the time to castration resistance, consistent with preclinical findings, and will be prospectively evaluated in future trials. See related commentary by Shenderov and Antonarakis, p. 5056 ., (©2020 American Association for Cancer Research.)

We report a case of rapid evolution of polycystic liver disease in a 76-year-old patient with metastatic renal cell carcinoma who underwent treatment with numerous antineoplastic agents. The aim was to identify a causative etiology for these hepatic cysts of unclear origin. The cystic lesions of the patient were ultimately innumerable and developed rapidly, more than tripling the total liver volume from complete absence over the course of 24 months. The hepatic lesions continued to grow despite an otherwise moderate tumor response. Prior to patient death, the patient remained relatively asymptomatic from the cyst burden and was without signs of grossly metastatic disease. This rapid development of polycystic liver disease most likely represents a previously unseen medication side-effect of cabozantinib or pazopanib. It is important to identify adverse effects of novel antineoplastic agents in this time of oncological medical discovery., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m 2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Androgen deprivation therapy (ADT) has been conventional treatment of newly diagnosed metastatic prostate cancer for more than 70 years. However, all patients eventually become castration-resistant and a significant proportion of life span is spent in the castration-resistant state. Prospective randomized control trials have incorporated early chemotherapy along with ADT based on the hypothesis that a significant level of resistance to ADT already exists in newly diagnosed metastatic prostate cancer and ADT exhibits synergistic antitumor activity with taxanes. We discuss the changing landscape of management of patients with newly diagnosed metastatic prostate cancer based on recently published landmark randomized trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade ≥ 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity.

Ever since the critical role of androgen deprivation therapy for the treatment of metastatic prostate cancer was established, several trials aimed to show an improved outcome with the early introduction of chemotherapy in metastatic disease. Until recently, all these trials-including the GETUG-AFU 15 trial-failed to confirm an improvement in survival. The recently published CHAARTED and STAMPEDE trials showed a striking benefit and changed the standard of care for patients with newly diagnosed metastatic prostate cancer. We summarize the evidence that emerged from these trials that support the use of combined chemohormonal therapy in metastatic hormone-sensitive prostate cancer.

Background: A phase 1/2a dose escalation study of APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) was conducted to determine maximum tolerated dose (MTD), recommended phase 2 dose, toxicities and efficacy in men with castrate-resistant prostate cancer (CRPC)., Methods: This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients in cohorts of 3 were treated with escalating doses of APC-100 (900 mg-2400 mg) orally once daily continuously. Cycles were 28 days., Results: Twenty patients with CRPC were enrolled in the dose escalation cohort. One possible DLT (elevated ALT) was seen at dose level 1. No other DLTs were seen and no dose reductions were required. Most frequent AEs included nausea (grade 1 in 6 patients) and elevated transaminases (grade 1-3 in 5 patients). After enrolment of 20 patients the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules ingested. Five of the 20 patients had stable disease as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1-8)., Conclusions: APC-100 is a novel agent with dual mechanism of action functioning both as potent antioxidant as well as antiandrogen. No detectable APC-100 was found in the plasma at dose level 5 (2100 mg) and it was felt that maximal feasibility was nearly reached. APC-100 is being reformulated as a tablet to allow further dose escalation. Once a recommended phase 2 dose is established, future studies in prostate cancer chemoprevention should be conducted.

Background: Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking., Patients and Methods: Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed., Results: Two thousand two hundred eighty-six patients were identified (sRCC: n = 230 and non-sRCC: n = 2056). sRCC patients had significantly worse IMDC prognostic criteria compared with non-sRCC (11% vs. 19% favorable risk; 49% vs. 57% intermediate risk, and 40% vs. 24% poor risk; P < .0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) was shorter in the sRCC group (18.8 vs. 42.9 months; P < .0001). There was no significant difference in the incidence of central nervous system metastases (6%-8%) or underlying clear cell histology (87%-88%). More than 93% of patients received VEGF inhibitors as first-line therapy; objective response was less common in sRCC whereas primary refractory disease was more common (21% vs. 26% and 43% vs. 21%; P < .0001, for both). sRCC patients had significantly less use of second- (P = .018) and third-line (P < .0001) systemic therapy. The median progression-free survival (PFS)/overall survival (OS) was 4.5/10.4 months in sRCC patients and 7.8/22.5 months in non-sRCC patients (P < .0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for individual IMDC risk factors in multivariable analysis (hazard ratio, 1.5; P < .0001 for both)., Conclusion: Patients with sRCC have a shorter time to relapse, worse baseline prognostic criteria, and worse clinical outcome with targeted therapy. Additional insight into the biology of sRCC is needed to develop alternative therapeutics., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: This study aims to make an indirect comparison between enzalutamide and abiraterone acetate for mCRPC post-docetaxel., Methods: A search for published phase 3 trials was performed with PubMed. Indirect comparisons of enzalutamide (AFFIRM) to abiraterone acetate (COU-AA-301) on outcomes overall survival (OS), time to prostate-specific-antigen (PSA) progression, radiographic progression-free survival (PFS), and PSA response were constructed in the context of log-linear regression models., Results: There was no statistically significant difference in OS (hazard ratio (HR) 0.85, 95% CI 0.68-1.07). However, there was some evidence that enzalutamide may outperform abiraterone acetate with respect to secondary outcomes: time to PSA progression (HR 0.40, 95% CI 0.30-0.53), radiographic PFS (HR 0.61, 95% CI 0.50-0.74), and PSA response rates (RRs) (OR 10.69, 95% CI 3.92-29.20)., Conclusion: While there was no statistically significant difference in OS, enzalutamide may be advantageous for secondary endpoints. Findings of this indirect comparison serve to be hypothesis-generating for future head-to-head trials.

Myeloid-derived suppressor cells (MDSCs) represent a heterogenous collection of immature myeloid cells endowed with suppressive function on the immune response. Their presence has been extensively investigated in preclinical models, especially in the context of cancer. One of the major obstacles in their accurate identification has been the definition of an unambiguous phenotype, shared between mice and humans, and clearly correlating with their suppressive function. In this paper, we review the literature concerning the phenotype in mouse and in humans, showing that at least 2 subsets of MDSCs are present under different situations. We also address the role of MDSCs in tumor progression, evaluate the prognostic significance of MDSC in cancer patients, and their possible role as marker of clinical outcome and response to therapy. Finally, we examine the strategies designed to modulate MDSCs in cancer patients, which might represent an innovative approach to enhance the effectiveness of immune-based therapies.

Studies exploring predictors of mortality in patients with ventilator-associated pneumonia (VAP) produced conflicting results. The present work is a meta-analysis of studies that enrolled only patients with microbiologically confirmed VAP and reported on mortality. Potentially eligible reports were searched in PubMed, EMBASE, CINAHL, and HEALTHSTAR with no language restrictions. Twenty-six reports were included. Factors associated with mortality were malignancy (odds ratio [OR], 2.20; 95% confidence interval [CI], 1.10-4.40) at intensive care unit admission as well as inappropriate initial treatment (i.e., treatment either in vitro inactive against the causative bacteria or administered later than 24 h after diagnosis of VAP) (OR, 2.92; 95% CI, 2.01-4.22), bacteremia (OR, 2.07; 95% CI, 1.16-3.71), acute respiratory distress syndrome/acute lung injury (OR, 2.28; 95% CI, 1.24-4.21), shock (OR, 3.90; 95% CI, 2.31-6.61), sepsis (OR, 4.77; 95% CI, 2.22-10.25), disease severity, and sepsis-related organ failure score at the day of diagnosis of VAP. Isolation of nonfermenting gram-negative bacteria in general (OR, 1.71; 95% CI, 1.09-2.68) and Acinetobacter baumannii in specific (OR, 1.74; 95% CI, 1.02-2.96) was also associated with higher fatality. Intensive care unit admission caused by trauma, as opposed to other reasons, was linked to lower mortality (OR, 0.35; 95% CI, 0.22-0.57). These findings may help investigators to formulate appropriate predicting scores for patients with VAP and may further motivate clinicians to provide appropriate initial treatment and to manage sepsis and shock optimally in such patients.