Publications by authors named "Yohann Loriot"

139 Publications

Safety and Efficacy of Atezolizumab in Understudied Populations with Pretreated Urinary Tract Carcinoma: Subgroup Analyses of the SAUL Study in Real-World Practice.

J Urol 2021 Apr 9:101097JU0000000000001768. Epub 2021 Apr 9.

San Camillo and Forlanini Hospitals, Rome, Italy (present address: Englander Institute for Precision Medicine, Weill Cornell Medicine, Meyer Cancer Center, New York, USA).

Purpose: Atezolizumab is an established treatment option for pretreated urothelial carcinoma, demonstrating efficacy in phase II/III trials. The SAUL study enrolled a broader patient population to determine safety and efficacy in under-represented subgroups.

Materials And Methods: Patients with metastatic urinary tract carcinoma received atezolizumab 1,200 mg every 3 weeks until disease progression, unacceptable toxicity, loss of clinical benefit or patient/physician decision. The primary endpoint was safety. Efficacy was a secondary endpoint. Analyses by PD-L1 status, age, ECOG performance status (PS) and renal impairment were prespecified; post hoc analyses explored outcomes by tumor location.

Results: 1004 patients were enrolled. Subgroup analyses in patients with older age, renal impairment or upper tract urothelial carcinoma showed safety and efficacy similar to those in patients without these characteristics. Patients with ECOG PS 2 had clinical features typically associated with aggressive disease; median overall survival was 2.3 months versus 10.0 months in patients with ECOG PS 0/1. Patients with PD-L1 expression on ≥5% of tumor-infiltrating immune cells tended to have better outcomes than those with <5% PD-L1 expression, although conclusions on the relative efficacy of atezolizumab cannot be drawn from this single-arm study.

Conclusions: The understudied populations included in the SAUL study had similar outcomes to those in more selected populations included in phase II/III trials of atezolizumab, except for those with ECOG performance status 2. Age ≥80 years and/or creatinine clearance <30 mL/min does not preclude administration of atezolizumab; however, treatment risk vs benefit must be carefully assessed in patients with ECOG PS 2.
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http://dx.doi.org/10.1097/JU.0000000000001768DOI Listing
April 2021

BCG-unresponsive high-grade non-muscle invasive bladder cancer: what does the practicing urologist need to know?

World J Urol 2021 Mar 27. Epub 2021 Mar 27.

University Hospital of Bicêtre-Paris Sud-Saclay University, Le Kremlin Bicêtre, Paris, France.

Purpose: Bacille Calmette-Guérin (BCG) is a well-established treatment for preventing or delaying tumour recurrence following high-grade nonmuscle invasive bladder cancer (NMIBC) resection. However, many patients will experience recurrence or progression during or following BCG. This scenario has been one of the most challenging in urologic oncology for several decades since BCG implementation. Finally, significant progress has occurred lately. The aim of this review was to summarize for the practising urologist the current treatment options available in 2020 or expected to be ready for routine use in the near future for patients with high-risk NMIBC who experience BCG failure.

Methods: Narrative review using data through the end of 2020.

Results: First, the definition of BCG unresponsive disease which is critical in counseling and managing patients has finally reached a consensus. Second, some promising options other than radical cystectomy are finally available and many other should be in a near future. The options can be categorized as chemotherapy, device-assisted therapy, check-point inhibitors, new intravesical and systemic agents and sequential combinations of these newer modalities with conventional therapy.

Conclusions: Considering the options that are currently under scrutiny, many of which in phase III trials, clinicians should have at their disposal several new treatment options in the next five years.
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http://dx.doi.org/10.1007/s00345-021-03666-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997797PMC
March 2021

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With or Without Panitumumab in Patients With Advanced Urothelial Carcinoma: Multicenter, Randomized, French Unicancer GETUG/AFU 19 Study.

Clin Genitourin Cancer 2021 Feb 24. Epub 2021 Feb 24.

Department of Pathology, René Huguenin Curie Institute, Saint Cloud, France.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm.

Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy.

Patients And Methods: Patients with advanced, treatment-naïve, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint.

Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors.

Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.
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http://dx.doi.org/10.1016/j.clgc.2021.02.005DOI Listing
February 2021

Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma.

N Engl J Med 2021 03 12;384(12):1125-1135. Epub 2021 Feb 12.

From Barts Cancer Centre, Queen Mary University of London, London (T.P.); Memorial Sloan Kettering Cancer Center, New York (J.E.R.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.P.S.); Gustave Roussy, Université Paris-Saclay, Villejuif, France (Y.L.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, Cantabria (I.D.), and Hospital Universitario 12 de Octubre, Madrid (D.C.) - both in Spain; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea (J.-L.L.); National Cancer Center Hospital East, Chiba, Japan (N.M.); the Center for Oncological Research, University of Antwerp, Integrated Cancer Center Ghent, Ghent, Belgium (C.V.); Astellas Pharma, Northbrook, IL (C.W., M.M.); Seagen, Bothell, WA (M.C.); and Smilow Cancer Center, Yale School of Medicine, New Haven, CT (D.P.P.).

Background: Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment.

Methods: We conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival.

Results: A total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively).

Conclusions: Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).
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http://dx.doi.org/10.1056/NEJMoa2035807DOI Listing
March 2021

Safety and Clinical Activity of Atezolizumab in Patients With Metastatic Castration-Resistant Prostate Cancer: a Phase I Study.

Clin Cancer Res 2021 Feb 10. Epub 2021 Feb 10.

Experimental Cancer Medicine Centre, Queen Mary University of London.

Purpose: Atezolizumab (anti-PD-L1) is well tolerated and efficacious in multiple cancers but not previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy and biomarkers of atezolizumab monotherapy for mCRPC.

Experimental Design: This phase Ia, open-label, dose-escalation and -expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously q3w until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.

Results: All 35 evaluable patients (median age, 68 years [range, 45-83 years]) received atezolizumab after {greater than or equal to}1 prior line of therapy; 62.9% of patients received {greater than or equal to}3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1 and one patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median OS was 14.7 months (95% CI: 5.9, not evaluable), with a 1-year OS rate of 52.3% (95% CI: 34, 70); 2-year OS was 35.9% (95% CI: 13, 59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.

Conclusions: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1981DOI Listing
February 2021

Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer.

Ther Adv Med Oncol 2020 23;12:1758835920978134. Epub 2020 Dec 23.

Department of Cancer Medicine, University of Paris Saclay, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, 94805, France.

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.
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http://dx.doi.org/10.1177/1758835920978134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768840PMC
December 2020

Immunodynamics of explanted human tumors for immuno-oncology.

EMBO Mol Med 2021 Jan 29;13(1):e12850. Epub 2020 Dec 29.

Institut Gustave Roussy, Villejuif, France.

Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.
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http://dx.doi.org/10.15252/emmm.202012850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799366PMC
January 2021

Partial Response and Stable Disease Correlate with Positive Outcomes in Atezolizumab-treated Patients with Advanced Urinary Tract Carcinoma.

Eur Urol Focus 2020 Nov 6. Epub 2020 Nov 6.

San Camillo and Forlanini Hospitals, Rome, Italy.

Background: The value of a complete response to immune checkpoint inhibitor treatment for urothelial cancer is well recognised, but less is known about long-term outcomes in patients with a partial response or the benefit of achieving disease stabilisation.

Objective: To determine clinical outcomes in patients with a partial response or stable disease on atezolizumab therapy for advanced urinary tract carcinoma (UTC).

Design, Setting, And Participants: Data were extracted from three prospective trials (IMvigor210 cohort 2, SAUL, and IMvigor211) evaluating single-agent atezolizumab therapy for platinum-pretreated advanced UTC. The analysis population included 604 atezolizumab-treated and 208 chemotherapy-treated patients (229 achieving a partial response and 583 achieving stable disease).

Intervention: Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity or single-agent chemotherapy for patients in the control arm of IMvigor211.

Outcome Measurements And Statistical Analysis: Baseline characteristics, treatment exposure, overall survival, duration of disease control. Partial response and stable disease populations were analysed separately.

Results And Limitations: The population of patients with a partial response included more patients with programmed cell death ligand 1 (PD-L1) expression on ≥5% of tumour-infiltrating immune cells than the stable disease population. The median time to best response was 2.1 mo across trials and treatments, regardless of the type of response. Atezolizumab-treated patients with a partial response had sustained disease control (median overall survival not reached); durations of disease control and overall survival were longer with atezolizumab than with chemotherapy. In patients with stable disease, median overall survival was numerically longer with atezolizumab (exceeding 1 yr) than with chemotherapy. Irrespective of treatment, durations of disease control and survival were shorter in patients with stable disease than in those achieving a partial response. These analyses are limited by their post hoc exploratory nature and relatively short follow-up.

Conclusions: Stable disease and partial response are meaningful clinical outcomes in atezolizumab-treated patients with advanced UTC.

Patient Summary: In this report, we looked at the outcomes in patients whose tumours responded to treatment to some extent, but the tumour did not disappear completely. We aimed to understand whether a modest response to treatment was associated with meaningful long-term outcomes for patients. We found that on average, life expectancy was >1 yr in patients whose disease was stabilised and even longer in those whose tumours showed some shrinkage in response to treatment.
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http://dx.doi.org/10.1016/j.euf.2020.10.009DOI Listing
November 2020

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial.

Lancet Oncol 2020 12 21;21(12):1574-1588. Epub 2020 Sep 21.

Beth Israel Deaconess Medical Center and PSMAR-IMIM Research Lab, Harvard Medical School, Boston, MA, USA.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.

Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.

Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury).

Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(20)30541-6DOI Listing
December 2020

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

NPJ Precis Oncol 2020 8;4:27. Epub 2020 Sep 8.

Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, 94800 Villejuif, France.

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.
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http://dx.doi.org/10.1038/s41698-020-00130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478969PMC
September 2020

Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

N Engl J Med 2020 09 18;383(13):1218-1230. Epub 2020 Sep 18.

From Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St. Bartholomew's Hospital, London (T.P.); Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Centre Jean Bernard Clinique Victor Hugo, Le Mans (E.V.), and Gustave Roussy, INSERM Unité 981, Université Paris-Saclay, Villejuif (Y.L.) - both in France; the Medical Oncology Unit, Azienda Ospedaliera S. Maria, Terni (C.C.), and Pfizer, Milan (C.F., A.P.) - both in Italy; the Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain (B.P.V.); the Department of Clinical Medicine, Macquarie University, Sydney (H.G.); the Division of Oncology, Department of Medicine, University General Hospital of Patras, Patras, Greece (H.K.); the Institute for Oncology and Radiology of Serbia, Belgrade (S.R.); the Department of Medical Oncology, Algemeen Ziekenhuis Klina, Brasschaat, Belgium (W.D.); Patient Area Pelvic Cancer, Theme Cancer, Karolinska University Hospital, and the Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden (A.U.); Princess Margaret Cancer Centre, University Health Network, Toronto (S.S.S.); the Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan (N.T.); the State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russia (E.K.); the Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York (C.N.S.); the Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (J.B.), and Pfizer, Cambridge (R.L., J.W.) - both in Massachusetts; Inova Schar Cancer Institute, Fairfax, VA (J.B.A.-C.); Yale Cancer Center, New Haven (D.P.P.), and Pfizer, Groton (B.H.) - both in Connecticut; Pfizer, La Jolla, CA (C.D., J.A.B.-H.); Pfizer, Porto Salvo, Portugal (N.C.); and the Department of Medicine, Division of Oncology, University of Washington, and the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle (P.G.).

Background: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.

Methods: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.

Results: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.

Conclusions: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).
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http://dx.doi.org/10.1056/NEJMoa2002788DOI Listing
September 2020

PIVOT-10: Phase II study of bempegaldesleukin plus nivolumab in cisplatin-ineligible advanced urothelial cancer.

Future Oncol 2021 Jan 17;17(2):137-149. Epub 2020 Sep 17.

Université Paris-Sud, Université Paris-Saclay, INSERM 981, Institute Gustave Roussy, 94 805 Villejuif Cedex, France.

The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).
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http://dx.doi.org/10.2217/fon-2020-0795DOI Listing
January 2021

Safety and efficacy of atezolizumab in patients with autoimmune disease: Subgroup analysis of the SAUL study in locally advanced/metastatic urinary tract carcinoma.

Eur J Cancer 2020 10 6;138:202-211. Epub 2020 Sep 6.

CREATE Centre, Section of Rheumatology, Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. Electronic address:

Aim: Patients with pre-existing autoimmune disease (AID) are typically excluded from clinical trials of immune checkpoint inhibitors, and there are limited data on outcomes in this population. The single-arm international SAUL study of atezolizumab enrolled a broader 'real-world' patient population. We present outcomes in patients with a history of AID.

Methods: Patients with locally advanced/metastatic urinary tract carcinoma received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary end-point was safety. Overall survival (OS) was a secondary end-point. Subgroup analyses of AID patients were prespecified.

Results: Thirty-five of 997 treated patients had AID at baseline, most commonly psoriasis (n = 15). Compared with non-AID patients, AID patients experienced numerically more adverse events (AEs) of special interest (46% versus 30%; grade ≥3 14% versus 6%) and treatment-related grade 3/4 AEs (26% versus 12%), but without relevant increases in treatment-related deaths (0% versus 1%) or AEs necessitating treatment discontinuation (9% versus 6%). Pre-existing AID worsened in four patients (11%; two flares in two patients); three of the six flares resolved, one was resolving, and two were unresolved. Efficacy was similar in AID and non-AID patients (median OS, 8.2 versus 8.8 months, respectively; median progression-free survival, 4.4 versus 2.2 months; disease control rate, 51% versus 39%).

Conclusions: In 35 atezolizumab-treated patients with pre-existing AID, incidences of special- interest and treatment-related AEs appeared acceptable. AEs were manageable, rarely requiring atezolizumab discontinuation. Treating these patients requires caution, but pre-existing AID does not preclude atezolizumab therapy.

Trial Registration: NCT02928406.
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http://dx.doi.org/10.1016/j.ejca.2020.07.023DOI Listing
October 2020

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with -Mutant Metastatic Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 Dec 28;26(23):6242-6253. Epub 2020 Aug 28.

Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France.

Purpose: The limited knowledge on the molecular profile of patients with -mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with -mutant NSCLC.

Experimental Design: This was a prospective study of 78 patients with advanced -mutant NSCLC, enrolled in 27 centers across France. Blood samples ( = 208) were collected from BRAF-TT-naïve patients ( = 47), patients nonprogressive under treatment ( = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.

Results: ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as -mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in , and .

Conclusions: ctDNA sequencing is clinically relevant for the detection of -activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in -mutant NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1037DOI Listing
December 2020

The FGFR3 Story in Bladder Cancer: Another Piece of the Puzzle?

Eur Urol 2020 11 25;78(5):688-689. Epub 2020 Aug 25.

Department of Medical Oncology, INSERM U981, Gustave Roussy, University Paris-Saclay, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2020.08.016DOI Listing
November 2020

[Immunotherapies in non-muscle invasive bladder cancer: immunotherapies and NMIBC].

Bull Cancer 2020 Jun;107(5S):S49-S55

Sorbonne Université, GRC n° 5, PRÉDICTIVE ONCO-URO, AP-HP, Urologie, Hôpital Pitié-Salpêtrière, F-75013 Paris, France.

Local and systemic immunotherapies are used for the management of bladder cancer in daily practice. BCG has been administered for almost 40 years in patients with non-muscle invasive bladder cancer (NMIBC). Despite its efficacy, disease progression is observed in nearly 30% of patients. Given the antitumor activity of immune checkpoint inhibitors in metastatic setting, these therapies are currently investigated in NMIBC. Pembrolizumab is now approved by the Food and Drug Administration (FDA) for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with carcinoma in situ with or without papillary tumors who are ineligible for or have not elected to undergo cystectomy. Several phase 3 trials are ongoing to investigate the efficacy of PD(L)1 inhibitors combined with BCG such as ALBAN study in France.
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http://dx.doi.org/10.1016/S0007-4551(20)30278-2DOI Listing
June 2020

Cutting-edge Management of Muscle-invasive Bladder Cancer in 2020 and a Glimpse into the Future.

Eur Urol Oncol 2020 12 15;3(6):789-801. Epub 2020 Jun 15.

Sorbonne University, GRC 5 Predictive ONCO-URO, AP-HP, Urology, Pitié-Salpêtrière Hospital, Paris, France. Electronic address:

This case-based discussion describes the clinical course of a 63-yr-old patient who presented with gross hematuria and was diagnosed with a muscle-invasive bladder cancer at transurethral resection. Computed tomography revealed a locally advanced tumor, and the patient underwent neoadjuvant chemotherapy followed by open radical cystectomy with standard pelvic lymph node dissection. In a step-by-step fashion, we elaborate on diagnostic and therapeutic treatment options from two different vantage points: (1) guideline-adherent treatment with the state-of-the-art standard of care, and (2) a glimpse into the future discussing the evidence of potential additional or alternative approaches based on recent scientific advances. PATIENT SUMMARY: In this case-based discussion, we follow the clinical course of a patient with advanced bladder cancer and elaborate how the state-of-the-art treatment looks like in 2020, based on the best available evidence. This is compared with potential future treatment strategies, which may change and alternate our understanding of optimal bladder cancer care.
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http://dx.doi.org/10.1016/j.euo.2020.06.001DOI Listing
December 2020

Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation.

J Clin Oncol 2020 09 18;38(26):3032-3041. Epub 2020 Jun 18.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA.

Purpose: Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.

Methods: EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an ≥ 0.7.

Results: Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.

Conclusion: EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.
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http://dx.doi.org/10.1200/JCO.19.03114DOI Listing
September 2020

Fibroblast growth factor receptors across urothelial carcinoma landscape.

Curr Opin Urol 2020 07;30(4):557-565

Department of Cancer Medicine, Gustave Roussy Institute, INSERM 981, Cancer Campus, Grand Paris, University of Paris-Saclay, Villejuif, France.

Purpose Of Review: Fibroblast growth factor receptor (FGFR) signalling, especially induced by FGFR3, is a crucial factor in the pathogenesis of urothelial carcinoma and was therefore extensively studied over the last decades. In this review, we summarize the most relevant findings of the past two years.

Recent Findings: Recent studies support the concept that FGFR3 mediates a pathway of urothelial carcinogenesis associated with low malignant potential. FGFR3 may represent a highly accurate biomarker for diagnosis and prediction of recurrence, progression or therapy response. The pan FGFR-inhibitor erdafitinib was recently approved for urothelial carcinoma, whereas several other FGFR-targeted drugs are currently undergoing clinical trials.

Summary: Numerous recent studies focus on the role of FGFR3 in different urothelial carcinoma subtypes and its potential clinical application as noninvasive biomarker, as well as therapeutic target.
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http://dx.doi.org/10.1097/MOU.0000000000000782DOI Listing
July 2020

Corrigendum to 'EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees' [European Urology 77 (2020) 223-250].

Authors:
J Alfred Witjes Marek Babjuk Joaquim Bellmunt H Maxim Bruins Theo M De Reijke Maria De Santis Silke Gillessen Nicholas James Steven Maclennan Juan Palou Tom Powles Maria J Ribal Shahrokh F Shariat Theo Van Der Kwast Evanguelos Xylinas Neeraj Agarwal Tom Arends Aristotle Bamias Alison Birtle Peter C Black Bernard H Bochner Michel Bolla Joost L Boormans Alberto Bossi Alberto Briganti Iris Brummelhuis Max Burger Daniel Castellano Richard Cathomas Arturo Chiti Ananya Choudhury Eva Compérat Simon Crabb Stephane Culine Berardino De Bari Willem De Blok Pieter J L De Visschere Karel Decaestecker Konstantinos Dimitropoulos Jose L Dominguez-Escrig Stefano Fanti Valerie Fonteyne Mark Frydenberg Jurgen J Futterer Georgios Gakis Bogdan Geavlete Paolo Gontero Bernhard Grubmüller Shaista Hafeez Donna E Hansel Arndt Hartmann Dickon Hayne Ann M Henry Virginia Hernandez Harry Herr Ken Herrmann Peter Hoskin Jorge Huguet Barbara A Jereczek-Fossa Rob Jones Ashish M Kamat Vincent Khoo Anne E Kiltie Susanne Krege Sylvain Ladoire Pedro C Lara Annemarie Leliveld Estefania Linares-Espinós Vibeke Løgager Anja Lorch Yohann Loriot Richard Meijer M Carmen Mir Marco Moschini Hugh Mostafid Arndt-Christian Müller Christoph R Müller James N'Dow Andrea Necchi Yann Neuzillet Jorg R Oddens Jan Oldenburg Susanne Osanto Wim J G Oyen Luís Pacheco-Figueiredo Helle Pappot Manish I Patel Bradley R Pieters Karin Plass Mesut Remzi Margitta Retz Jonathan Richenberg Michael Rink Florian Roghmann Jonathan E Rosenberg Morgan Rouprêt Olivier Rouvière Carl Salembier Antti Salminen Paul Sargos Shomik Sengupta Amir Sherif Robert J Smeenk Anita Smits Arnulf Stenzl George N Thalmann Bertrand Tombal Baris Turkbey Susanne Vahr Lauridsen Riccardo Valdagni Antoine G Van Der Heijden Hein Van Poppel Mihai D Vartolomei Erik Veskimäe Antoni Vilaseca Franklin A Vives Rivera Thomas Wiegel Peter Wiklund Peter-Paul M Willemse Andrew Williams Richard Zigeuner Alan Horwich

Eur Urol 2020 Jul 21;78(1):e48-e50. Epub 2020 May 21.

Emeritus Professor, The Institute of Cancer Research, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2020.03.017DOI Listing
July 2020

Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAF non-small cell lung cancer.

Eur J Cancer 2020 06 6;132:211-223. Epub 2020 May 6.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France.

Introduction: BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAF NSCLC.

Patients And Methods: Patients with BRAF NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array.

Results: Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb).

Conclusions: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2020.03.025DOI Listing
June 2020

Adjustments in the Use of Intravesical Instillations of Bacillus Calmette-Guérin for High-risk Non-muscle-invasive Bladder Cancer During the COVID-19 Pandemic.

Eur Urol 2020 Jul 24;78(1):1-3. Epub 2020 Apr 24.

Sorbonne University, GRC 5 Predictive onco-uro, APHP, Urology, Pitié-Salpétrière Hospital, 75013 Paris, France. Electronic address:

Non-muscle-invasive bladder cancer patients with COVID-19 are more likely to develop acute respiratory distress syndrome. Thus, several adjustments to the use of intravesical instillations of bacillus Calmette-Guérin should be made during the current pandemic to limit the risk of contamination.
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http://dx.doi.org/10.1016/j.eururo.2020.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180366PMC
July 2020

Long-term Castration-related Outcomes in Patients With High-risk Localized Prostate Cancer Treated With Androgen Deprivation Therapy With or Without Docetaxel and Estramustine in the UNICANCER GETUG-12 Trial.

Clin Genitourin Cancer 2020 Dec 7;18(6):444-451. Epub 2020 Apr 7.

Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France. Electronic address:

Introduction: Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects.

Patients And Methods: Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected.

Results: Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms.

Conclusion: Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery.
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http://dx.doi.org/10.1016/j.clgc.2020.03.017DOI Listing
December 2020

Genetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model.

Nat Commun 2020 04 20;11(1):1884. Epub 2020 Apr 20.

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. A CTC-derived eXplant (CDX) and a CDX-derived cell line are established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis from a CRPC patient resistant to enzalutamide. The CDX and the derived-cell line conserve 16% of primary tumor (PT) and 56% of CTC mutations, as well as 83% of PT copy-number aberrations including clonal TMPRSS2-ERG fusion and NKX3.1 loss. Both harbor an androgen receptor-null neuroendocrine phenotype, TP53, PTEN and RB1 loss. While PTEN and RB1 loss are acquired in CTCs, evolutionary analysis suggest that a PT subclone harboring TP53 loss is the driver of the metastatic event leading to the CDX. This CDX model provides insights on the sequential acquisition of key drivers of neuroendocrine transdifferentiation and offers a unique tool for effective drug screening in CRPC-NE management.
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http://dx.doi.org/10.1038/s41467-020-15426-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171138PMC
April 2020

Liver tests increase on abiraterone acetate in men with metastatic prostate cancer: Natural history, management and outcome.

Eur J Cancer 2020 04 6;129:117-122. Epub 2020 Mar 6.

Gustave Roussy, Université Paris-Saclay, Oncology Medicine Department, Villejuif, F-94805, France. Electronic address:

Background: Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described.

Patients And Method: We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France.

Results: Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose.

Conclusion: Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.
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http://dx.doi.org/10.1016/j.ejca.2020.01.017DOI Listing
April 2020

Neuroendocrine Carcinoma of the Urinary Bladder: A Large, Retrospective Study From the French Genito-Urinary Tumor Group.

Clin Genitourin Cancer 2020 08 5;18(4):295-303.e3. Epub 2019 Dec 5.

Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France; Association pour la Recherche et les Thérapeutiques Innovantes en Cancérologie, Paris, France; University René Descartes, Paris, France.

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.

Materials And Methods: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.

Results: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.

Conclusions: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.
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http://dx.doi.org/10.1016/j.clgc.2019.11.014DOI Listing
August 2020

Studying Rarity in Bladder Cancer.

Eur Urol 2020 04 5;77(4):447-448. Epub 2019 Dec 5.

Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.11.018DOI Listing
April 2020

EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort: Under the Auspices of the EAU-ESMO Guidelines Committees.

Authors:
J Alfred Witjes Marek Babjuk Joaquim Bellmunt H Maxim Bruins Theo M De Reijke Maria De Santis Silke Gillessen Nicholas James Steven Maclennan Juan Palou Tom Powles Maria J Ribal Shahrokh F Shariat Theo Van Der Kwast Evanguelos Xylinas Neeraj Agarwal Tom Arends Aristotle Bamias Alison Birtle Peter C Black Bernard H Bochner Michel Bolla Joost L Boormans Alberto Bossi Alberto Briganti Iris Brummelhuis Max Burger Daniel Castellano Richard Cathomas Arturo Chiti Ananya Choudhury Eva Compérat Simon Crabb Stephane Culine Berardino De Bari Willem De Blok Pieter J L De Visschere Karel Decaestecker Konstantinos Dimitropoulos Jose L Dominguez-Escrig Stefano Fanti Valerie Fonteyne Mark Frydenberg Jurgen J Futterer Georgios Gakis Bogdan Geavlete Paolo Gontero Bernhard Grubmüller Shaista Hafeez Donna E Hansel Arndt Hartmann Dickon Hayne Ann M Henry Virginia Hernandez Harry Herr Ken Herrmann Peter Hoskin Jorge Huguet Barbara A Jereczek-Fossa Rob Jones Ashish M Kamat Vincent Khoo Anne E Kiltie Susanne Krege Sylvain Ladoire Pedro C Lara Annemarie Leliveld Estefania Linares-Espinós Vibeke Løgager Anja Lorch Yohann Loriot Richard Meijer M Carmen Mir Marco Moschini Hugh Mostafid Arndt-Christian Müller Christoph R Müller James N'Dow Andrea Necchi Yann Neuzillet Jorg R Oddens Jan Oldenburg Susanne Osanto Wim J G Oyen Luís Pacheco-Figueiredo Helle Pappot Manish I Patel Bradley R Pieters Karin Plass Mesut Remzi Margitta Retz Jonathan Richenberg Michael Rink Florian Roghmann Jonathan E Rosenberg Morgan Rouprêt Olivier Rouvière Carl Salembier Antti Salminen Paul Sargos Shomik Sengupta Amir Sherif Robert J Smeenk Anita Smits Arnulf Stenzl George N Thalmann Bertrand Tombal Baris Turkbey Susanne Vahr Lauridsen Riccardo Valdagni Antoine G Van Der Heijden Hein Van Poppel Mihai D Vartolomei Erik Veskimäe Antoni Vilaseca Franklin A Vives Rivera Thomas Wiegel Peter Wiklund Andrew Williams Richard Zigeuner Alan Horwich

Eur Urol 2020 02 19;77(2):223-250. Epub 2019 Nov 19.

Emeritus Professor, The Institute of Cancer Research, London, UK.

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 prior to 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), and 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 statements, 33 (28%) achieved level 1 consensus and 49 (42%) 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 when further evidence is available to guide our approach.

Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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http://dx.doi.org/10.1016/j.eururo.2019.09.035DOI Listing
February 2020

Clinical outcome after progressing to frontline and second-line Anti-PD-1/PD-L1 in advanced urothelial cancer.

Eur Urol 2020 02 5;77(2):269-276. Epub 2019 Nov 5.

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Immune checkpoint inhibitors (ICIs) are approved for first-line (cisplatin unfit, PD-L1+) and platinum-refractory urothelial carcinoma (UC). Still, most patients experience progressive disease (PD) as the best response. Although higher response rates to subsequent systemic treatment (SST) have been described, post-PD outcome data are scarce.

Objective: To examine the outcome of UC patients who received SST and no SST after progressing to ICIs.

Design, Setting, And Participants: A retrospective analysis of UC patients progressing to frontline or later-line anti-PD-1/PD-L1 therapy in 10 European institutions was conducted between March 2013 and September 2017.

Intervention: Post-PD management as per standard practice.

Outcome Measurements And Statistical Analysis: Overall survival (OS) was analyzed with a Kaplan-Meier model. Cox regression was used for multivariate analysis (MV). Impact of SST on OS was examined with a time-varying covariate model.

Results And Limitations: A total of 270 UC patients with PD to ICIs (69 frontline, 201 later line) were analyzed. Of the patients, 57% of frontline-ICI-PD and 34% of later-line-ICI-PD patients received SST, and SST had an impact on OS in MV (frontline: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.10-0.51, p <  0.001; later line: HR 0.22, 95% CI 0.13-0.36, p <  0.001). In the frontline-ICI-PD group, median OS with and without SST was 6.8 mo (95% CI 5.0-8.6) and 1.9 mo (95% CI 0.9-3.0), respectively. High disease burden (three or more metastatic sites: HR 2.49, p =  0.03; simultaneous liver/bone metastases: HR 3.93, p =  0.03) predicted worse survival. In later-line-ICI-PD group, response to ICIs (HR 0.37, p =  0.03), longer exposure to ICIs (HR 0.89, p =  0.002), and bone metastasis (HR 2.42, p <  0.001) predicted survival. The retrospective nature of this study and a lack of certain parameters limit the interpretation of our analysis.

Conclusions: Patients progressing to frontline ICIs are at risk of early death, excluding them from experiencing potential benefit from chemotherapy PATIENT SUMMARY: Our analysis suggests that outcomes after failing immunotherapy are poor, particularly in UC patients who received no prior chemotherapy.
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http://dx.doi.org/10.1016/j.eururo.2019.10.004DOI Listing
February 2020

Erdafitinib in Urothelial Carcinoma. Reply.

N Engl J Med 2019 10;381(16):1594-1595

University of Texas M.D. Anderson Cancer Center, Houston, TX

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http://dx.doi.org/10.1056/NEJMc1911187DOI Listing
October 2019