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Background: Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells., Materials and Methods: INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety., Results: Eighty-five patients were included and randomized to arm A (n = 42) and arm B (n = 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (P = 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, P = 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, P = 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found., Conclusions: The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214., Patients and Methods: Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients., Results: With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time., Conclusions: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301., Materials and Methods: Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety., Results: In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%., Conclusions: After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC., Materials and Methods: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR)., Results: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks 1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown)., Conclusions: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Pulmonary embolism (PE) represents one of the leading causes of death worldwide and mainly treated with medical management, although the utility of more invasive approaches has emerged more recently. This meta-analysis aims to evaluate the 30-day mortality of intermediate-to-high risk PE across different treatment strategies., Methods: A systematic literature review and meta-analysis was conducted using PubMed and Cochrane databases. All studies reporting 30-day mortality rates in intermediate-to-high-risk PE were included. Meta-regression analysis and sensitivity analysis were performed on the primary endpoint, 30-day mortality, and secondary endpoints (RV/LV ratio, mPAP, and long-term mortality, any bleeding events)., Results: Of the 2390 studies published between 2000 and 2022, 76 studies (74 observational and 2 RCTs for a total of 1,194,285 patients in the medical cohort and 3007 in the interventional cohort) were included. The median age was 71.4 (IQR 62.8-77.3) years, 53.6% were women. 30-day mortality in the patients treated with medical management was 9.1% (6.6-12.6). In the interventional cohort, 30-day mortality was 2.1% (1.5-3.1) while the pre- vs post-procedure change in mean difference was -6.1 mmHg (-11.2 to -1.1) for mPAP and - 0.41 (-0.51 to - 0.31) for RV/LV ratio. The overall bleeding rate in the interventional cohort was 4.9% (CI 2.6-8.9), without differences between the two strategies (RR 1.26 CI 0.89-1.78)., Conclusion: Intermediate-high-risk mortality in pulmonary embolisms treated with medical management remains high in the modern era. Despite the absence of comparative studies, an interventional approach may have a lower 30-day mortality rate and a good safety profile., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear., Methods: A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted., Results: The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients)., Conclusion: Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit., Competing Interests: Declaration of Competing Interest This research did not receive additional support from an organization beyond the authors’ academic institutions. Guillermo de Velasco: GDV is supported by ISCIII-AES-2021 PI21/01922 Consulting and advisory services from Pfizer, Novartis, Bayer, Roche, Ipsen, Astellas Pharma, Bristol-Myers Squibb, MSD and Merck; research funding from Ipsen; and Honoraria, travel and accommodation expenses from Pfizer, Ipsen, Bristol-Myers-Squibb, Astellas Pharma and Roche; Daniel Castellano: Consulting or Advisory Role—Astellas Pharma; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Ipsen; Janssen Oncology; Lilly; MSD Oncology; Novartis; Pfizer; Pierre Fabre; Roche/Genentech; Sanofi; Roberto Iacovelli: Advisory Board member—Astellas, BMS, EISAI, IPSEN, Janssen, MSD, Novartis, Pfizer, Sanofi. Consultant for Astellas, EISAI, MSD, Pfizer; Laurence Albiges: Consulting/advisory role—BMS, Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb, Bayer, and Cerulean; research funding—Pfizer and Novartis. Rest of authors including corresponding author confirm no other conflict of interest to disclose. The authors declare there are no patents to disclose. The authors declare there are not addition relationships or activities to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns., Patients and Methods: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary end point was objective response rate (ORR) per RECIST v1.1 by BICR., Results: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. Median follow-up was 62.9 months (range, 58.6-70.9; data cutoff October 1, 2020). At 48 months, OS rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; PFS rates were 9.5% and 2.7%, respectively. Median duration of response (DOR) was 29.7 months (range, 1.6+ to 60.5+) for pembrolizumab and 4.4 months (range, 1.4+ to 63.1+) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. Median follow-up was 56.3 months (range, 51.2-65.3; data cutoff September 26, 2020). Confirmed ORR was 28.9% (95% CI, 24.3-33.8), and median DOR was 33.4 months (range, 1.4+ to 60.7+); 36-month DOR rate was 44.8%. Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports., Conclusion: With approximately 5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients. Clinical trial registry and ID: ClinicalTrials.gov, NCT02256436 (KEYNOTE-045) and NCT02335424 (KEYNOTE-052)., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC., Patients and Methods: We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors., Results: We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months., Conclusion: Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI., Methods: We identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd + line., Results: We identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd + line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd + line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant., Conclusion: Bone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer., Patients and Methods: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m 2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety., Results: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia)., Conclusions: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted., Competing Interests: Disclosure VB received grants as consultant or advisory role from Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart; honoraria as speaker from Eli Lilly; and institutional financial support for clinical trials from AbbVie, ACEO, Adaptaimmune, Amcure, AMGEN, AstraZeneca, BMS Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, GSK, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, and Zenith. BP received consulting fees from AstraZeneca and Pfizer for her institution and from Myriad and Pierre Fabre for herself; payment or honoraria for lectures, presentations, speakers bureaus or educational events from Daiichi-Sankyo, Novartis and Puma; support for attending meetings and/or travel from AstraZeneca, Pierre Fabre and MSD; and participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Astra Zeneca and Daiichi-Sankyo. VM received grants or contracts as principal investigator or institutional funding from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics and Upshersmith; consulting fees from Roche, Bayer, BMS, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Bayer, BMS; and participation on a Data Safety Monitoring Board or Advisory Board from Basilea. CF, CK, VA, MS and AZ have personal fees for salary as full time employees from PharmaMar S.A. CF, CK, VA and AZ are stock ownership of PharmaMar S.A. FL received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from Roche, Merck, Amgen, Lilly, Servier, MSD, BMS and Sanofi. AA received consulting fees from Gilead, Lilly and Seagen; payment for expert testimony from Pfizer; and leadership or fiduciary role in ECO Foundation. VS received grants from PharmaMar, Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics and Boston Pharmaceuticals; and grants from Helsinn Pharmaceuticals during the conduct of the study; in addition, VS received a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, PharmaMar and Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Relay therapeutics, Roche and Medimmune; travel funds from PharmaMar, Incyte, ASCO, ESMO; and other support from Medscape, all outside the submitted work. All other authors have declared no conflicts of interest. Data Sharing Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrollment in 2015. Clinical trial summary results were placed in the European Clinical Trials Database (EudraCT; https://eudract.ema.europa.eu; study 2014-003773-42) and ClinicalTrials.gov (identifier: NCT02454972)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies., Patients and Methods: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate., Results: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib., Conclusion: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens., Competing Interests: Disclosure EG has received honoraria for speaker engagements, advisory roles, or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, GSK, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, Thermo Fisher Scientific. TAG has received support for the present manuscript (protocol review and manuscript review); has received research grants from Pfizer, Roche, and Ipsen; has received consulting fees from Ipsen, Pfizer, Roche, Sanofi, Bayer, Astellas, Janssen-Cilag, BMS, and EISAI; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Eisai, and Merck; has received support for attending meetings and/or travel from Pfizer, Sanofi, BMS, and IPSEN. OR has received personal payment from Eusapharma, BMS, Pfizer, and Ipsen; has received support for attending meetings and/or travel from Ipsen and Pfizer; has participated in the Advisory Board of BMS and Bayer. XGdM has received consulting fees from Roche, Pharmamar, BMS, Ipsen, Lilly, Eusapharma, Pfizer, Merck, and Astellas; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS, Astellas, Pharma, Eisai, Pfizer, and EusaPharma; has received support for attending meetings and/or travel from Pfizer and Roche; and has received research funding from AstraZeneca. MJM has received payment or honoraria as invited speaker from Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Norvartis, Pfizer, and MSD; has received travel support from Roche and Ipsen; has participated on Data Safety Monitoring Board or Advisory Board of Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis, Pfizer, and MSD. JGD has received grants or contracts from Eusapharma, Bristol Myers, Novartis, GSK, Merck, MSD, Sanofi, Janssen, Astellas, Astra Zeneca, and Ipsen; has received support for attending meetings and/or travel from Roche; has participated on a Data Safety Monitoring Board or Advisory Board from Pfizer and Pharmamar. MGR has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche; has received support for attending meetings and/travel from Roche, Ipsen, AstraZeneca, MSD, and Jansen. JAAA has received grants or contracts from Bristol-Myers Squibb (grant to Spanish GU Oncology Group for research in prostate cancer); has received consulting fees from Janssen, Cilag, Pfizer, MSD, and Bristol-Myers Squibb; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, Pfizer, and MSD; has received support for attending meetings and/or travel from MSD, Bristol-Myers Squibb, and Astra Zeneca. PLC has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD and Bristol; has participated on a Data Safety Monitoring Board or Advisory Board from Sanofi and Roche. JMC has received support for the present manuscript (protocol review and manuscript review); has received grants or contracts from Pfizer and Ipsen; has received consulting fees from Ipsen, Pfizer, Roche, Sanofi, Astellas, Janssen Cilag, BMS, and EISAI; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, and BMS; and has received support for attending meetings and/or travel from Pfizer, BMS, and Ipsen. BM has received research grant/funding (self) from Jansen, Roche, Astellas, Sanofi, and Bayer; has received payment or honoraria for speaker bureau from Pfizer, Ipsen, Jansen, Roche, Astellas, Sanofi, BMS, and Bayer; has received support for travel accommodation from Pfizer, Ipsen, Janssen, and Roche; other financial or non-financial interests: advisory and speaker bureau rom Pfizer, Ipsen, Jansen, Roche, Astellas, Sanofi, BMS, and Bayer; travel accommodation from Pfizer, Ipsen, Jansen, and Roche; and research grant/funding (self) from Roche, Astellas, Sanofi Jansen, BMS, and Bayer. CAF has received consulting fees from Ipsen, Boehringer Ingelheim, and Astra Zeneca; has received support for attending meetings and/or travel from Roche, Pfizer, and Astellas. GDV has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Pfizer, Roche, Merk, MSD, Bayer, Eusapharma, Astellas, and Ipsen; has received support for attending meetings and/or travel from Roche; has participated on a Data Safety Monitoring Board or Advisory Board from BMS, Pfizer, Roche, Merck, MSD, Bayer, and Astellas. JFRM has received support for the present manuscript from Pfizer; has received grants or contracts from HM Hospitales; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, BMS, Novartis, and MSD; has received support for attending meetings from Pfizer, BMS, Novartis, and MSD; has participated on a Data Safety Monitoring Board or Advisory Board from BMS and Novartis; and has participated in corporate-sponsored research in his institution from AstraZeneca, BMS, Amgen, Roche, Novartis, MSD, Janssen, Pfizer, Astellas, GSK, PharmaMar, Ipsen, Tesaro, Abbvie, Aprea Therapeutics, Eisai, Bayer, and Merck. CSR has received grants or contracts from AB Science, Aragon Pharmaceuticals, Astellas Pharma, Astra Zeneca AB, Bayer, Blueprint Medicines Corporation, Boehringer Ingelheim España SA, BMS, Clovis Oncology, Exelixix Inc F, Genentech Inc, GlaxoSmithKline SA, Hoffman-La Roche LTD, Novartis Farmaceutica SA, Pfizer SLU, and Sanofi-Aventis; has received payment or honoraria for speakers’ bureau from Astellas Pharma, BMS, Hoffmann-La Roche LTD, Ipsen, Pfizer SLU; has participated on a Data Safety Monitoring Board or Advisory Board from Astellas Pharma, Bayer, BMS, Eusapharma, Hoffmann-La Roche LTD, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis E. All other authors have declared no conflicts of interest. Data sharing The clinical trial data are available from the corresponding author upon reasonable request., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) improve overall survival (OS) in patients with locally advanced, unresectable, or metastatic urothelial carcinoma (aUC), but response rates can be modest. We compared outcomes between patients with and without prior intravesical Bacillus Calmette-Guerin (BCG), who received ICI for aUC, hypothesizing that prior intravesical BCG would be associated with worse outcomes., Patients and Methods: We performed a retrospective cohort study across 25 institutions in US and Europe. We compared observed response rate (ORR) using logistic regression; progression-free survival (PFS) and OS using Kaplan-Meier and Cox proportional hazards. Analyses were stratified by treatment line (first line/salvage) and included multivariable models adjusting for known prognostic factors., Results: A total of 1026 patients with aUC were identified; 614, 617, and 638 were included in ORR, OS, PFS analyses, respectively. Overall, 150 pts had history of prior intravesical BCG treatment. ORR to ICI was similar between those with and without prior intravesical BCG exposure in both first line and salvage settings (adjusted odds radios 0.55 [P= .08] and 1.65 [P= .12]). OS (adjusted hazard ratios 1.05 [P= .79] and 1.13 [P= .49]) and PFS (adjusted hazard ratios 1.12 [P= .55] and 0.87 [P= .39]) were similar between those with and without intravesical BCG exposure in first line and salvage settings., Conclusion: Prior intravesical BCG was not associated with differences in response and survival in patients with aUC treated with ICI. Limitations include retrospective nature, lack of randomization, presence of selection and confounding biases. This study provides important preliminary data that prior intravesical BCG exposure may not impact ICI efficacy in aUC., (Copyright © 2021. Published by Elsevier Inc.)

Background: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified., Patients and Methods: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed., Results: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data., Conclusions: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker., Patients and Methods: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m 2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS., Results: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608)., Conclusions: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR., Competing Interests: Disclosure RdW provided an advisory role for Sanofi, Janssen, Merck, Bayer, and Astellas, and received institutional grants from Sanofi and Bayer. DC has received personal fees from Pfizer, Roche, Sanofi, Janssen, Astellas, Bayer, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Merck Serono, Pierre Fabre, AstraZeneca, and Lilly. GK received personal fees from Sanofi, Astellas, Takeda, Bayer, Janssen, Novartis, Ipsen, and AstraZeneca, and has received grants from Sanofi and Bayer. J-CE has received honoraria from and provided an advisory role for Astellas, BMS, Ipsen, Janssen, Pfizer, and Sanofi Aventis, and has received travel and accommodation fees from Pfizer and BMS. CNS has received honoraria from Janssen, AstraZeneca, Sanofi and Astellas, received consultancy fees from Sanofi, Bayer, and Pfizer, and received institutional funding from Genentech/Roche, Bayer, Sanofi Genzyme, Janssen, Medivation, MSD, and Exelixis. KF has received honoraria and provided an advisory role for Astellas, AAA Pharmaceutical Inc, Bayer, Essa, Janssen, Orion, CureVac, Clovis, Sanofi, and Endocyte. BT has received personal fees and research grants from Astellas, Janssen, Sanofi Genzyme, Amgen, and Ferring, and received non-financial support from Sanofi Genzyme. AB has received honoraria and research support from and provided an advisory role to Astellas, Janssen, and Sanofi. JC has provided an advisory role for Astellas, AstraZeneca, Bayer, BMS, MSD Oncology, Johnson & Johnson, Sanofi, Roche, and Pfizer, and has attended speaker bureaus for Asofarma, Astellas, Bayer, and Johnson & Johnson. RI received honoraria and provided an advisory role for Sanofi, Janssen, Pfizer, Ipsen, Novartis, BMS, and MSD. BM received travel fees, honoraria, and provided an advisory role for BMS and Merck Serono, and received honoraria and provided an advisory role for MSD, Sanofi, Roche, Janssen, Bayer, Astellas, Amgen, Novartis, Servier, AstraZeneca, Eisai, E. Lilly, Ipsen, Pierre Fabre, and Pfizer. CH has received consultancy fees from Sanofi, Janssen, and Astellas. MCF and CG-R are employees of Sanofi. AO is an employee and stockholder of Sanofi. JdB has received honoraria from AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, and BioXcel Therapeutics, and provided an advisory role for AstraZeneca, Sanofi, Genentech/Roche, Astellas Pharma, Bayer, Pfizer, MSD, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Menarini Silicon Biosystems, Celgene, Taiho Pharmaceutical, Daiichi Sankyo, Janssen Oncology, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Eisai, and BioXcel Therapeutics. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immune-checkpoint inhibitor-based therapy has revolutionized the natural history of metastatic renal cell carcinoma (mRCC) providing better survival outcomes, higher rates of complete responses (CR) and durable remissions. Along with these advances, new challenges have emerged. RECIST and new immune-response criteria may be equivocal identifying complete responses. How to define a durable response and what is the optimal treatment duration remains unclear. Furthermore, the real value of a complete and deep response, whether or not it can be considered curation and whether or not immunotherapy discontinuation should be considered after complete response, are questions that remain open. The present article reviews the current evidence regarding the impact and challenges of managing complete and durable responses in mRCC treated with immune-checkpoint inhibitors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The impact of pretreatment factors on immune checkpoint inhibition in platinum-refractory advanced urothelial cancer (aUC) deserves further evaluation. The aim was to study the association of Bellmunt risk factors, time from last chemotherapy (TFLC), previous therapy and PD-L1 expression with atezolizumab efficacy in platinum-refractory aUC., Patients and Methods: This was a post-hoc analysis of patients who had received prior cisplatin or carboplatin in the prospective, single-arm, phase IIIb SAUL study (NCT02928406). Patients were treated with 3-weekly atezolizumab 1200 mg intravenously. The primary outcome was overall survival (OS). Relationships were analysed using Cox regression and long-rank test., Results: Of 997 patients in SAUL, 969 were eligible for this analysis. The number of Bellmunt risk factors was associated with OS (P < 0.001); median OS (mOS) for 0, 1 and 2-3 risk factors was 17.9, 8.9 and 3.3 months, respectively. Significant associations were also observed between OS and TFLC (P < 0.001), programmed death-ligand 1 (PD-L1) expression (P = 0.002), and prior perioperative chemotherapy (P = 0.013); mOS was 6.97 versus 11.63 months for TFLC ≤6 versus >6 months, 7.75 versus 11.6 months for PD-L1 expression on <1% of tumour-infiltrating immune cells (ICs) (IC0)/expression on 1% to <5% of tumour-infiltrating ICs (IC1) versus expression on ≥5% of tumour-infiltrating ICs (IC2/3) and 10.2 versus 7.8 months for prior versus no prior perioperative chemotherapy, respectively. The type of platinum compound and number of previous treatment lines were not associated with outcomes., Conclusions: Post-platinum atezolizumab is active in aUC, irrespective of previous platinum compound and lines of therapy. Bellmunt risk stratification, PD-L1 expression, TFLC and perioperative chemotherapy were identified as prognostic factors for OS with second-line atezolizumab, indicating the need for novel prognostic signatures for immunotherapy-treated patients with aUC., Competing Interests: Disclosure AB: honoraria, advisory and research funding from Roche, BMS, MSD, Ipsen, Debiopharm, Basilea, Pierre Fabre and Janssen; and steering committee member for Roche. ASM: lectures/speaker honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Astellas, Novartis, Pfizer and Roche; consultant for AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSA Pharma, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer and Roche; research and clinical trials support from AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSA Pharma, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer and Roche. YL: personal fees from Roche, Janssen, Astellas, MSD, Pfizer, Roche, BMS, Immunomedics, AstraZeneca, Sanofi and Seattle Genetics; grants from Janssen, MSD and Sanofi; non-financial support from Janssen, Roche, AstraZeneca and Sanofi. NJ: consultancy from Merck, Roche and AstraZeneca; trial funding (to institution) from Merck, Roche and AstraZeneca. EC: research grants from Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB; consultancy from AbbVie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm and Sanofi; and speakers fees from AbbVie, Amgen, Bristol Myer Squibb, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB. DC: personal fees for advisory boards/speaker engagements from Roche, Janssen, Astellas, MSD, Ipsen, Pfizer, Bristol-Myers Squibb, Bayer, AstraZeneca, Novartis, Lilly, Sanofi, Pierre Fabre and Boehringer Ingelheim. FL-R: honoraria from AstraZeneca, Bayer, BMS, Lilly, MSD, Pfizer, Roche and Thermo Fisher; and research funding from Lilly, Roche and Thermo Fisher. FC: advisory role for BMS, MSD, Pfizer and AstraZeneca. MK: honoraria/consultation for Bayer, BMS, EUSAI, Novartis, Merck, MSD, Pfizer and Roche; travel grants from Ipsen, Janssen, Merck and Novartis. GdeV: support for clinical trials and scientific projects for Pfizer, Roche and Ipsen; and speaker fees and consulting for Pfizer, Novartis, Roche, MSD, Astellas, Bayer, Ipsen, Janssen, Merck, EUSA Pharma and BMS. CNS: consultant for Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, BMS, Foundation Medicine, Immunomedics (now Gilead), Medscape, UroToday, CCO Clinical, Janssen and NCI. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nivolumab-ipilimumab has become the standard of care in the frontline setting for intermediate-/poor-risk metastatic renal cell carcinoma (mRCC). This regimen is associated with survival improvement but significant toxicity. Anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) monotherapy may provide response and offers a better safety profile. In this context, nivolumab-ipilimumab has been postulated as a rescue treatment after anti-PD-1/PD-L1 therapy. Recent retrospective data has shown positive results, and several nonrandomized clinical trials (NRCTs) have evaluated this strategy. Therefore, we performed a meta-analysis of available NRCTs to clarify the efficacy and safety of salvage nivolumab-ipilimumab in mRCC after prior anti-PD-1/PD-L1 monotherapy. We searched PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials to identify clinical trials investigating the efficacy and safety of salvage nivolumab-ipilimumab after prior anti-PD-1/PD-L1 in patients with mRCC. Only phase II NRCTs were available for the analysis. The pooled effect of single proportions with a 95% confidence interval (CI) was used as the measure of effect (overall response rate [ORR] and incidence of grade ≥ 3 adverse events). Four studies accounting for 237 patients were included. All patients received prior anti-PD-1/PD-L1 monotherapy. The pooled ORR of salvage nivolumab-ipilimumab after prior anti-PD-1/PD-L1 failure was 10.0% (95% CI, 6%-14%; I 2  = 41%; P = .17). The incidence of grade ≥ 3 irAEs was 27.0% (95% CI, 20%-35%; I 2  = 0%; P = .56). The results of this analysis suggest that the use of salvage nivolumab-ipilimumab in mRCC after prior anti-PD-1/PD-L1 has limited activity with a 10% ORR, and a non-negligible toxicity with 1 of 4 patients developing grade ≥ 3 immune-related adverse events., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Urothelial bladder cancer (UC) is the most common malignancy involving the urinary system and represents a significant health problem. Immunotherapy has been used for decades for UC with intravesical bacillus Calmette-Guérin (BCG) set as the standard of care for non-muscle-invasive bladder cancer (NMIBC). The advent of immune checkpoint inhibitors (ICIs) has completely transformed the treatment landscape of bladder cancer enabling to expand the treatment strategies. Novel ICIs have successfully shown improved outcomes on metastatic disease to such an extent that the standard of care paradigm has changed leading to the development of different trials with the aim of determining whether ICIs may have a role in early disease. The localized muscle-invasive bladder cancer (MIBC) scenario remains challenging since the recurrence rate continues to be high despite all therapeutic efforts. This article will review the current experience of ICIs in the neoadjuvant setting of UC, the clinical trials landscape and finally, an insight of what to expect in the immediate and mid-term future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC)., Methods: Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory)., Results: Overall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN., Conclusion: After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety., Trial Registration Details: ClinicalTrials.gov identifier: NCT02231749., Competing Interests: Competing interests: LA reports consulting fees from Pfizer, Novartis, Bristol Myers Squibb (BMS), Ipsen, Roche, MSD, AstraZeneca, Merck, Amgen, Astellas and Exelixis; and other fees from Corvus Pharmaceuticals and Peloton Therapeutics. NMT reports research funding from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Arrowhead Pharmaceuticals, Mirati Therapeutics, Takeda, Epizyme and Eisai Medical Research; consulting and advisory fees from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical and Oncorena; and travel accommodations and expenses from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical and Oncorena. MB reports advisory and speaker fees from Roche, MSD, BMS, AstraZeneca and Sanofi. DM reports research funding from BMS, Merck, Genentech/Roche, Novartis, Peloton Therapeutics, Alkermes and Prometheus Laboratories; consulting or advisory fees from BMS, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, X4 Pharma, Array BioPharma, Peloton Therapeutics, EMD Serono, Jounce Therapeutics, Alkermes and Lilly; and other fees from Beth Israel Deaconess Medical Center. ERP reports research funding (institutional) from BMS, AstraZeneca, Merck, Peloton Therapeutics, Pfizer and Astellas; consulting fees from AstraZeneca, BMS, Genentech, Merck, Pfizer, Clovis, Exelixis, Incyte, Seattle Genetics, Janssen, Flatiron Health, Infinity Pharma and McKesson; fees for development of educational presentations from BMS and Merck; and US Patent Application No. 14/588,503. PB reports consulting or advisory fees from BMS, Pfizer, MSD Oncology, Novartis, Ipsen, Roche and Janssen Cilag; travel accommodations and expenses from Amgen; and honoraria from Astellas Pharma. CP reports consulting or advisory fees from BMS, MSD, Pfizer, Ipsen Eusa, Eisai and General Electric; speaker fees from BMS, MSD, Pfizer, Ipsen, Eusa, Eisai, General Electric, Janssen and AstraZeneca; research funding from Pfizer; expert testimony fees from Pfizer and Eusa; and travel accommodations and expenses from Roche. TP reports consulting fees from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck/MSD, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai and Roche; honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck/MSD, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai and Roche; research funding (institutional) from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson and Eisai; and travel accommodations and expenses from Roche, Pfizer, MSD, AstraZeneca and Ipsen. FD reports research funding (institutional) from MSD, Pfizer and Ipsen. SG reports research funding from Bayer, BMS, Pfizer, Novartis, Corvus, Pfizer, Acceleron, Merck, Agensys, Seattle Genetics, Calithera, Immunomedics, Corvus and Eisai; and consulting or advisory fees from Bayer, BMS, Exelixis, Corvus, Genentech, Sanofi/Genzyme, Pfizer, Seattle Genetics, Eisai, Merck and EMD Serono. CKK reports advisory board fees from Janssen, Astellas, Pfizer, Ipsen, Eisai, Roche, Merck and BMS; and lecture fees from Pfizer, Ipsen, Eisai and BMS. HG reports advisory board fees from Pfizer, Astellas, Ipsen, Roche and BMS. M-OG reports research funding from Novartis, BMS and Intuitive Surgical; advisory fees from Novartis, BMS, Pfizer, Bayer HealthCare, Astellas, Intuitive Surgical, AstraZeneca, MSD, Janssen Cilag, ONO Pharmaceutical, Ipsen Pharma and Merck Serono; and lecture fees from Novartis, BMS, Pfizer, Astellas, Hexal, Apogepha, AstraZeneca, MSD, ONO Pharmaceutical, Ipsen Pharma, Medac and Merck Serono. YT reports research funding from ONO Pharmaceutical, Pfizer and Takeda; consulting or advisory fees from ONO Pharmaceutical; and honoraria from ONO Pharmaceutical, BMS and Pfizer. DC reports research funding (institutional) from Janssen Oncology; consulting or advisory fees from Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Novartis, Ipsen, BMS, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre and Boehringer Ingelheim; and travel accommodations and expenses from Pfizer, Roche, BMS and AstraZeneca Spain. BIR reports research funding from Pfizer, Merck, GNE/Roche, Aveo, AstraZeneca and BMS; consulting fees from BMS, Pfizer, GNE/Roche, Aveo, Novartis, Synthorx, Peloton, Compugen, Merck, Arravive, Surface Oncology and 3D Medicines; and stock ownership in PTC therapeutics. TKC reports clinical trial grants from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; consulting or advisory fees from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; manuscript preparation fees from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; travel accommodations and expenses from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; and patent related to biomarkers of immune-oncology and cfmethDNA pending. SSS is an employee of and has stock ownership in BMS. MBM is an employee of and has stock ownership in BMS. RJM reports research funding (institutional) from Pfizer, Novartis, Eisai, Genentech, Roche and BMS; and consulting or advisory fees from Pfizer, Novartis, Eisai, Exelixis, Merck, Genentech, Incyte, Lilly, Roche and BMS., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness., Methods: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing., Findings: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality., Interpretation: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments., Funding: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nanofibrous scaffolds composed of polycaprolactone (PCL) and gelatin (Ge) were obtained through a hydrolytic assisted electrospinning process. The PCL-to-Ge proportion (100/0 to 20/80), as well as the dissolution time (24, 48, 72, 96, 120 h) into a 1:1 formic/acetic acid solvent before electrospinning were modified to obtain the different samples. A strong influence of these factors on the physicochemical properties of the scaffolds was observed. Higher Ge percentage reduced crystallinity, allowed a uniform morphology and increased water contact angle. The increase in the dissolution time considerably reduced the molar mass and, subsequently, fibre diameter and crystallinity were affected. During in vitro biocompatibility tests, higher cell adhesion and proliferation were found for the 60/40, 50/50 and 40/60 PCL/Ge compositions that was corroborated by MTT assay, fluorescence and microscopy. A weakened structure, more labile to the in vitro degradation in physiologic conditions was found for these compositions with higher dissolution times (72 and 96 h). Particularly, the 40/60 PCL/Ge scaffolds revealed an interesting progressive degradation behaviour as a function of the dissolution time. Moreover, these scaffolds were non-inflammatory, as revealed by the pyrogen test and after the 15-day subcutaneous in vivo implantation in mice. Finally, a reduction of the scar tissue area after infarction was found for the 40/60 PCL/Ge scaffolds electrospun after 72 h implanted in rat hearts. These results are especially interesting and represent a feasible way to avoid undesired inflammatory reactions during the scaffold assimilation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial., Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management., Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference., Setting: Online Delphi survey and consensus conference., Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management., Outcome Measurements and Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus)., Results and Limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease., Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Although increasing numbers of therapies with proven survival benefits have become available for metastatic castration-resistant prostate cancer (mCRPC), including radium-223, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses., Materials and Methods: This study was a translational study that was conducted prospectively by the Spanish Oncology Genito-Urinary Group and included 45 patients with histologically confirmed mCRPC who were treated with radium-223. The primary response outcome was defined by a decline in circulating tumor cells (CTCs) of > 50% from baseline or a CTC count of ≤ 5 cells/7.5 mL at cycle 3 of radium-223. We also assessed response according to prostate-specific antigen and alkaline phosphatase levels. CTCs were evaluated as prognostic factor for treatment completion with radium-223 treatment. Kaplan-Meier estimates of survival were calculated for the global population and were correlated with biomarker response outcomes., Results: Significantly, more patients with baseline CTC counts ≤ 5/7.5 mL, which are indicative of better prognoses, completed the 6 injections of therapy than those with CTC counts > 5 (16/22; 73% vs. 6/20; 30%, respectively; P = .012). The median overall survival was 16 months. Survival was significantly decreased in patients with baseline CTC counts > 5 cells/7.5 mL (7 months; P = .026) and baseline alkaline phosphatase levels ≥ 220 U/L (8 months; P = .028)., Conclusions: CTCs hold significant promise as a prognostic factor for survival and completing treatment prior to the initiation of bone-targeted radium-223 therapy. These findings may help to guide the use of radium-223 in patients with mCRPC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population., Methods: We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m 2 , paclitaxel 175 mg/m 2 , or 75 mg/m 2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807., Findings: Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6-15·5; n=116] vs 10·6 months [8·4-12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63-1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6-13·2]; HR 0·57, 95% CI 0·26-1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients)., Interpretation: Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting., Funding: F Hoffmann-La Roche, Genentech., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population., Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125., Findings: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab., Interpretation: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma., Funding: Eli Lilly and Company., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients., Patients and Methods: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS., Results: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms., Conclusions: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort., Methods and Materials: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses., Results: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy., Conclusions: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC., Methods: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial)., Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P < 0.001 and HR 3.81; 95% CI 2.28-6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts., Conclusion: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required., Clinical Trial Number: NCT02288936 (PREMIERE trial)., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib., Patients and Methods: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses., Results: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib., Conclusions: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib., Trial Registration Number: NCT00428597., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population., Methods: For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652., Findings: Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study., Interpretation: Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma., Funding: F Hoffmann-La Roche Ltd., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs., Methods: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated., Results: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]., Conclusions: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201)., Clinical Trial Number: NCT01280201., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups., Patients and Methods: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS)., Results: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable)., Conclusion: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC)., Patients and Methods: The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib., Results: High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023)., Conclusions: We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.

Targeted agents have improved prognosis for patients with metastatic renal cell carcinoma (mRCC), and they are changing therapeutic expectations with respect to long-term clinical outcomes for these patients. However, in order to obtain the maximum clinical benefit from targeted agents, effective therapy management is essential and includes optimization of dosing and treatment duration, as well as adequate side-effect management. Sunitinib has demonstrated efficacy for the treatment of patients with mRCC and is a reference standard of care for first-line therapy. However, in clinical practice, it is difficult to determine the best treatment strategy with targeted agents due to long-term tolerability and the development of resistance. An individualized therapeutic strategy in RCC requires a comprehensive understanding of the biology of response and resistance to targeted therapy. Here we review the clinical data regarding the efficacy and safety for sunitinib and highlight the importance of therapy management, as well as the potential use of clinical biomarkers in order to maximize the clinical benefit from sunitinib treatment in patients with mRCC., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The field of urothelial carcinoma has shown considerable advances in terms of diagnosis, staging, and treatment. The increasing knowledge of molecular pathways and genes involved in the occurrence of this tumor has encouraged the search for new, more effective and less toxic therapies, and has prompted the design and development of clinical trials. However, the speed at which results are published makes it difficult for clinicians to cover the vast amount of information available. Moreover, in clinical practice some gaps remain concerning treatment options for patients who have progressed after first-line cisplatin-based combinations, who cannot tolerate cisplatin-based chemotherapy, or who have received platinum-based neoadjuvant or adjuvant therapy, and thus cannot be offered this option on disease progression. The purpose of this review is to issue a series of recommendations on the optimal management of early and advanced urothelial carcinoma based on current evidence and the available updated guidelines., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer., Methods: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392., Findings: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm., Interpretation: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma., Funding: Pfizer Inc., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: A strong rationale supports the role of antiangiogenic drugs in urothelial cancer. This trial was designed to assess the activity of sunitinib as first-line treatment in patients with metastatic urothelial cancer ineligible for cisplatin and to explore molecular and imaging variables predictive of clinical benefit., Patients and Methods: This was a multicenter phase II trial with sunitinib 50 mg daily in 4/2-week schedule. Eligibility criteria were as follows: creatinine clearance 30-60 ml/min, Eastern Cooperative Oncology Group Pperformance Sstatus of one or less, and adequate hepatic and hematologic function. Twelve circulating cytokines were evaluated at baseline and sequentially using Luminex xMAP(®) (Austin, TX). Baseline and treatment-related changes in perfusion were evaluated in a patient subgroup using contrast-enhanced computed tomography., Results: On intention-to-treat analysis, 38 patients showed 3 (8%) partial responses (PRs) and 19 (50%) presented with stable disease (SD), 17 (45%) of them ≥3 months. Clinical benefit (PR + SD) was 58%. Median time to progression (TTP) was 4.8 months and median overall survival 8.1 months. Toxicity was consistent with previous reports for sunitinib. Low interleukin-8 (IL-8) baseline levels were significantly associated with increased TTP. Baseline tumor contrast enhancement with >40 Hounsfield units was associated with clinical benefit., Conclusions: This study highlights the potential role of the angiogenic pathway as a therapy target in urothelial cancer. Baseline IL-8 serum levels and contrast enhancement of lesions warrant further study.

Background: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country., Patients and Methods: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers., Results: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival., Conclusion: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.

Background: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-alpha) treatment in patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: In all, 304 mRCC patients (European cohort) were randomized 1 : 1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-alpha (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index and the EuroQol Group's EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included., Results: Results consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values., Conclusions: Results from MEM showed the sunitinib's benefit on HRQoL compared with IFN-alpha.

Background: The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose of a combination of vinorelbine plus gemcitabine administered on a biweekly schedule in patients with advanced solid tumors., Patients and Methods: Patients with advanced or refractory solid tumors included in this phase I study were treated with vinorelbine followed by gemcitabine. Vinorelbine was given intravenously over 10 min, and gemcitabine was given intravenously at an fixed-dose infusion rate of 10 mg/m(2)/min. Six dose levels of vinorelbine/gemcitabine were explored: 20/2000, 25/2500, 25/3000, 30/3000, 30/3500 and 30/2500 mg/m(2)., Results: Nineteen patients were included in the study. Fourteen patients were pretreated with chemotherapy and/or radiotherapy. A total of 123 cycles of chemotherapy were administered. DLTs were neutropenic fever and grade 3 asthenia at dose level 5 (30/3500 mg/m(2)); at dose level 4 (30/3000 mg/m(2)) they were grade 3 asthenia, and a radiation-recall reaction and pneumonitis. Sixteen patients were evaluable for efficacy. Five patients had an objective response (one complete response and four partial responses), for an overall response rate of 31%., Conclusions: The recommended dose for phase II study is vinorelbine 30 mg/m(2) and gemcitabine 2500 mg/m(2) administered once every 2 weeks. This regimen is feasible and well-tolerated at this dose, and shows a good clinical activity in all levels explored.

Background: The aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)., Methods: Seventy patients with previously untreated stage III-IV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m(2) as a 3-h infusion on day 1, cisplatin 100 mg/m(2) on day 2, and 5-fluorouracil (5-FU) 500-750 mg/m(2)/day as a 24-h continuous infusion on days 2-6, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m(2)/day to 500 mg/m(2)/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery., Results: Two-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 2-3, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 40-63 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively., Conclusions: The PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.

The natural product dehydrozaluzanin C (former DHZ) is a sesquiterpene lactone obtained from different weeds of the Compositae family. Its potential as a plant growth regulator has been evaluated by using a phytotoxic allelopathic bioassay, where the commercial herbicide Logran is used as internal reference. The evaluation is made based on their effects on germination and growth over several dicotyledon and monocotyledon species. The activity was tested in the range of 1000-0.001 microM. In almost all cases, DHZ was more active than the internal reference at 1000 microM, and its activity fell below the level of the internal reference at 100 microM. These results confirm DHZ as a potent plant growth regulator and a good candidate for the development of new herbicide models.

Background: To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck., Patients and Methods: Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks., Results: Twenty-four patients with a median age of 59 years (range 42-74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%-42%). The main toxicity was hematological: neutropenia grade 3-4 in 28% of the cycles and thrombocytopenia grade 3-4 in 16%. The most significant non-hematological toxicity was asthenia grade 2-3 in 24% of the cycles., Conclusions: This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.

Background: The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine plus cisplatin, administered every three weeks, in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Twenty-six previously untreated stages III (14) and IV (12) patients were included. Gemcitabine was administered on days 1 and 8 at a dose of 1250 mg/m2 and cisplatin was administered at a dose of 100 mg/m2 on day 1, every 21 days., Results: Twenty-five patients were evaluable for response. One patient achieved a complete response, and 16 patients partial responses. The overall response rate was 65.3% (95% CI: 45%-82%). The main toxicity was hematological: neutropenia NCIC-CTC grade 3-4 in 54% of the patients, and thrombocytopenia grade 3-4 in 23%. The non-hematological toxicity was mild and tolerable. Only 13% of gemcitabine injections were dose-reduced or omitted due to toxicity. The actual dose-intensity of gemcitabine was 715 mg/m2/week, and 31 mg/m2/week for cisplatin. These figures represent the 86% and 93% of the theoretical dose intensity of both drugs, respectively. With a median follow-up of 10 months (range 7-13), 17 patients are still alive and nine have died. The median overall survival is 12 months., Conclusion: This novel combination of gemcitabine and cisplatin administered every three weeks is well tolerated and induces a remarkably high response rate. The regimen proves more interesting than the four-week schedules, particularly regarding patients who are candidates for local therapy.