Advanced Bladder Cancer COE Articles

Articles

  • A Randomized Phase II Trial of Vinflunine and Gemcitabine Versus Carboplatin and Gemcitabine in Cisplatin-Ineligible Patients with Advanced Urothelial Carcinoma - Expert Commentary

    A significant number of patients with locally advanced and metastatic urothelial cancer (aUC) are not eligible for cisplatin-based chemotherapy.
    Published January 16, 2020
  • An Update on Muscle Invasive Bladder Cancer and Metastatic Bladder Cancer

    Introduction

    Bladder cancer was one of the top five leading causes of cancer death in 2015.1 Most of these cases are of urothelial histologic origin. For about 35% of patients, bladder cancer is either muscle-invasive or metastatic at disease presentation. In addition, non-muscle invasive disease can progress to become muscle-invasive bladder cancer later on in the disease course. Preceding chapters discussed the diagnosis and staging of bladder cancer.  This chapter will focus on the management of muscle-invasive urothelial bladder cancer as well as metastatic bladder cancer.

    Muscle Invasive Bladder Cancer

    Patients with muscle-invasive bladder cancer have the best outcomes when they are treated with a multidisciplinary approach. 

    Neoadjuvant Chemotherapy
    Neoadjuvant cisplatin-based regimens improve survival outcomes for patients with invasive bladder cancer.2,3 This has been shown in randomized trials and meta-analyses.4-9 The Advanced Bladder Cancer Meta-analysis Collaboration found a significant disease (9%) and overall survival (5%) benefit with platinum-based chemotherapy regimens.2  A recently updated meta-analysis (2016) with mature data on these randomized clinical trials revealed a 13% improvement in survival.3 Thus, neoadjuvant chemotherapy should be offered to all patients with muscle-invasive disease.

    In patients who are not eligible for cisplatinum-based regimens (eg. creatinine clearance (<60 ml/min), ECOG performance status ≥2, New York Heart Association class ≥III heart failure, grade ≥2 hearing loss, ≥2 neuropathy, proceeding directly to extirpative local therapy or XRT is sometimes appropriate.10 Among the chemotherapy regimens studied, the most effective are MVAC: methotrexate, vinblastine, doxorubicin, and cisplatin and GC: Gemcitabine and Cisplatinum (note: there is no role for Carboplatin in this disease). There has been no head to head studies but some meta-analyses have shown a decreased survival benefit for GC when compared to dose-dense MVAC. Dose-dense MVAC is tolerated well and offers the advantage of shortened time for waiting to undergo surgery.11-13  Additional advantages of neoadjuvant chemotherapy include the downstaging with ≤pT1N0 (49%).12 These chemotherapy regimens not only provide an improved overall survival but also are associated with a complete pathologic response in about 25%-30% of patients.12,14 In the future molecular subtypes may play a role in determining which patients would benefit from neoadjuvant chemotherapy.15,16 For example, Seiler et al found that tumors classified as basal tumors had the most improvement in overall survival with neoadjuvant chemotherapy.15 These studies remain hypothesis generating at this point;  studies to validate them are needed before they can be used in clinical practice. Until that time we, at MD Anderson, use a risk-adapted approach to avoid chemotherapy in patients who might derive minimal benefit.17 This strategy is shown in Figure 1.17


    diagram-muscle-invasive-bladder-cancer@2x.jpg


    Culp et al. performed a retrospective study to define in high-risk muscle-invasive bladder cancer (≥cT3b or histologic lymphovascular invasion, micropapillary or neuroendocrine features) patients who underwent chemotherapy and compared outcomes in those who did and did not undergo neoadjuvant chemotherapy.18 This study concluded that patients who are most likely to benefit from chemotherapy are those who are high risk due to the worse prognosis compared to low-risk muscle-invasive bladder cancer.18

    A few studies have evaluated the role of immunotherapy in the neoadjuvant setting. The ABACUS trial showed a downstaging of 39% and a pathologic complete response in 29% of patients 19 The PURE study also showed a pathologic complete response in 40% of patients and downstaging in 51%.20

    Radical Cystectomy
    Radical cystectomy with urinary diversion is an essential part of the curative strategy for patients with non-metastatic bladder cancer. It is a complex surgery and is often associated with morbidity; however, enhanced recovery (ERAS) programs have helped improve patient’s surgical course outcomes.21,22 ERAS programs focus on the preoperative, intraoperative, and postoperative continuum of care. Preoperative phases focus on preparation physically and mentally for surgery. Intraoperative phases work to decrease postoperative infection and limit fluid overload. Lastly, postoperative efforts are focused on early self-care and ambulation and feeding allowing for early discharge. An integral medication has been alvimopan (Entereg) in reducing the GI-related toxicity induced by opioid medications in the perioperative setting.23

    Radical cystectomy should include a bilateral pelvic lymph node dissection, this should include at a minimum the standard node dissection: internal iliac, external iliac, an obturator with consideration of an extended node template in high-risk patients (to include common iliac, presacral lymph nodes).24 While several retrospective studies have shown the importance of removing more lymph node, we await the results of SWOG trial S1011 to answer whether an extended lymph node dissection is truly needed.25-29

    The approach to surgery (whether open or robotic) is less important than the skill of the surgeon.30 The International Radical Cystectomy Consortium has reported that robotic cystectomy and diversions can be performed with similar outcomes to open surgery.31  The recent randomized trial comparing open to robotic cystectomy (RAZOR) showed no difference in intermediate oncologic outcomes.31 While operative time was longer with the robotic approach, there was reduced blood loss and transfusions, and shorter hospital stay.31 To date there no randomized trials comparing intracorporeal urinary diversion to open urinary diversion.

    Partial cystectomy is only appropriate in a highly selected patient population such as tumor only in a bladder diverticulum or urachal adenocarcinoma. 24

    Urinary Diversion
    The choice of urinary diversion is an important, life-altering one for patients undergoing radical surgery.32 Common urinary diversions include the ileal conduit, right-sided colon pouch (Indiana pouch) and orthotopic neobladder. Most studies have found no difference in the quality of life for the different urinary diversions, however, females may have a greater decrease in quality of life compared to men.33-35 There are certain factors which may limit continent urinary diversions such as dexterity, cognition, previous radiation, preexisting incontinence and bladder tumor proximity to the urethra. Patients should have skills to manage their urinary diversion prior to discharge from the hospital after cystectomy.24

    Trimodal Therapy
    Trimodal therapy (TMT) with chemotherapy, radiation and maximal TURBT offers a curative option to appropriately selected patients with radical cystectomy as a salvage option.36,37 It is also an option in patients with multiple medical comorbidities,  or those unwilling to undergo radical cystectomy.38  Traditional selection criteria for TMT are patients with no variant histology, minimal T2 disease, no tumor associated hydronephrosis and absence of carcinoma-in-situ.38,39  Patients should not always be offered radiation in conjunction with chemotherapy when the goal is curative intent.40 A recent large retrospective study from the NCDB using a propensity-matched analysis found median overall survival 2.7 years (RC) vs 3 years (TMT).41 However, another study using the SEER-Medicare database also using a propensity-matched analysis found that radical cystectomy was less expensive and had better survival compared to TMT with almost 50% worse overall and cancer-specific survival.42

    Adjuvant Treatments

    Adjuvant Chemotherapy
    In patients with high-risk features such as ≥T3 disease and/or ≥N1 may benefit from adjuvant chemotherapy.43,44 In a recent systematic review and meta-analysis of over 1500 patients from 11 clinical trials.43 There was significant progression-free and overall survival associated with adjuvant chemotherapy compared with radical cystectomy alone with a 35% improvement in progression-free survival and 20% improvement in overall survival.43 An additional retrospective study by Galsky et al also showed a benefit in overall survival.44 Adjuvant chemotherapy regimens have been studied with the addition of adjuvant radiation, this found improved two year outcomes of locoregional recurrence-free survival of 96% compared to those without adjuvant chemotherapy and RT of 69%.45 Patients who are chemotherapy naïve seem to benefit more than patients who underwent neoadjuvant chemotherapy.46 The most benefit is again seen with cisplatinum containing regimens.47

    Adjuvant Radiotherapy
    Adjuvant radiotherapy has had limited success due to toxicity to normal structures (eg bowel), but renewed interest has shown there may be a potential role for adjuvant radiation after radical cystectomy in high-risk patients and this is an ongoing area of study.48-51 Baumann et al and Reddy et al have both published data on the contouring and target volumes of adjuvant radiation in patients after cystectomy to help alleviate some of the previous issues with post-cystectomy anatomical changes. In addition, there are multiple ongoing trials of adjuvant therapy in patients with ≥T3 disease.50

    Metastatic Urothelial Cancer

    Chemotherapy
    Cisplatin-based regimens remain the mainstay of treatment for patients that are eligible for chemotherapy.52 The area of immunotherapy in metastatic urothelial cancer is rapidly expanding.53 In addition, for elderly patients, cisplatin-based chemotherapy regimens can be difficult to tolerate and carry a high rate of patient elected discontinuation.54 For these reasons, immunotherapy may provide a treatment option for those who cannot tolerate cisplatin therapy.

    Surgery
    In select patients who have responded to chemotherapy, surgery may be a reasonable step, however, this is based on retrospective data, thus selection bias must heavily influence the decision on which patients may benefit from salvage surgery.55 Salvage surgery may have a higher likelihood of complications, however, this has not been an area well studied. Surgical consolidation may be reasonable in patients who have a good response to chemotherapy and have small lesions. 56 In addition, metastasectomy has been shown to be effective in solitary pulmonary lesions in retrospective studies.55,57 In a SEER-Medicare study, a select group of patients underwent metastasectomy and over one third were still alive at three years, thus prolonging cancer survival.58 In a meta-analysis, survival was improved by 37% with a metastasectomy.59

    Immunotherapy
    There has been a recent deluge in the realm of immunotherapy.60 Multiple drugs have been approved with agents available for patients who fail cisplatinum therapy as second-line therapy and in those who are cisplatin-ineligible patients as first-line treatment (Table 1), .61 Combinations of immunotherapy with traditional chemotherapy are currently being investigated.

    table-1-muscle-invasive-bladder-cancer@2x.jpg


    It is noteworthy that the administration of these immunotherapeutic agents has also been associated with multiple forms of immune-mediated reactions (colitis, pneumonitis, thyroiditis, hypophysitis, etc.) that can be life-threatening.  Patients undergoing immunotherapy have to be watched vigilantly for adverse immune-mediated reactions, if not addressed immediately, these can lead to serious adverse outcomes.

    Published Date: April 16th, 2019

    Written by: Janet Baack Kukreja, MD, MPH and Ashish Kamat, MD, MBBS
    References:
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    19. Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). Journal of Clinical Oncology. 2018;36(15_suppl):4506-4506.
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    29. von Landenberg N, Speed JM, Cole AP, et al. Impact of adequate pelvic lymph node dissection on overall survival after radical cystectomy: A stratified analysis by clinical stage and receipt of neoadjuvant chemotherapy. Urol Oncol. 2018;36(2):78 e13-78 e19.
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    31. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. Lancet. 2018;391(10139):2525-2536.
    32. Hautmann RE, Abol-Enein H, Lee CT, et al. Urinary diversion: how experts divert. Urology. 2015;85(1):233-238.
    33. Ziouziou I, Irani J, Wei JT, et al. Ileal conduit vs orthotopic neobladder: Which one offers the best health-related quality of life in patients undergoing radical cystectomy? A systematic review of literature and meta-analysis. Prog Urol. 2018;28(5):241-250.
    34. Tyson MD, 2nd, Barocas DA. Quality of Life After Radical Cystectomy. Urol Clin North Am. 2018;45(2):249-256.
    35. Siracusano S, D'Elia C, Cerruto MA, et al. Quality of Life in Patients with Bladder Cancer Undergoing Ileal Conduit: A Comparison of Women Versus Men. In Vivo. 2018;32(1):139-143.
    36. Gofrit ON. Re: Long-Term Outcomes in Patients with Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. Eur Urol. 2015;68(1):165-166.
    37. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014;32(34):3801-3809.
    38. Smelser WW, Austenfeld MA, Holzbeierlein JM, Lee EK. Where are we with bladder preservation for muscle-invasive bladder cancer in 2017? Indian J Urol. 2017;33(2):111-117.
    39. Gakis G, Efstathiou J, Lerner SP, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2013;63(1):45-57.
    40. Hafeez S, McDonald F, Lalondrelle S, et al. Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment. Int J Radiat Oncol Biol Phys. 2017;98(1):115-122.
    41. Zhong J, Switchenko J, Jegadeesh NK, et al. Comparison of Outcomes in Patients With Muscle-invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder Preservation. Am J Clin Oncol. 2018.
    42. Williams SB, Shan Y, Jazzar U, et al. Comparing Survival Outcomes and Costs Associated With Radical Cystectomy and Trimodal Therapy for Older Adults With Muscle-Invasive Bladder Cancer. JAMA Surg. 2018;153(10):881-889.
    43. Kim HS, Jeong CW, Kwak C, Kim HH, Ku JH. Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized clinical trials. Oncotarget. 2017;8(46):81204-81214.
    44. Galsky MD, Stensland KD, Moshier E, et al. Effectiveness of Adjuvant Chemotherapy for Locally Advanced Bladder Cancer. J Clin Oncol. 2016;34(8):825-832.
    45. Zaghloul MS, Christodouleas JP, Smith A, et al. Adjuvant Sandwich Chemotherapy Plus Radiotherapy vs Adjuvant Chemotherapy Alone for Locally Advanced Bladder Cancer After Radical Cystectomy: A Randomized Phase 2 Trial. JAMA Surg. 2018;153(1):e174591.
    46. Sui W, Lim EA, Joel Decastro G, McKiernan JM, Anderson CB. Use of Adjuvant Chemotherapy in Patients with Advanced Bladder Cancer after Neoadjuvant Chemotherapy. Bladder Cancer. 2017;3(3):181-189.
    47. Pouessel D, Bastuji-Garin S, Houede N, et al. Adjuvant Chemotherapy After Radical Cystectomy for Urothelial Bladder Cancer: Outcome and Prognostic Factors for Survival in a French Multicenter, Contemporary Cohort. Clin Genitourin Cancer. 2017;15(1):e45-e52.
    48. Baumann BC, Bosch WR, Bahl A, et al. Development and Validation of Consensus Contouring Guidelines for Adjuvant Radiation Therapy for Bladder Cancer After Radical Cystectomy. Int J Radiat Oncol Biol Phys. 2016;96(1):78-86.
    49. Reddy AV, Christodouleas JP, Wu T, Smith ND, Steinberg GD, Liauw SL. External Validation and Optimization of International Consensus Clinical Target Volumes for Adjuvant Radiation Therapy in Bladder Cancer. Int J Radiat Oncol Biol Phys. 2017;97(4):740-746.
    50. Baumann BC, Sargos P, Eapen LJ, et al. The Rationale for Post-Operative Radiation in Localized Bladder Cancer. Bladder Cancer. 2017;3(1):19-30.
    51. Baumann BC, He J, Hwang WT, et al. Validating a Local Failure Risk Stratification for Use in Prospective Studies of Adjuvant Radiation Therapy for Bladder Cancer. Int J Radiat Oncol Biol Phys. 2016;95(2):703-706.
    52. Bamias A, Tiliakos I, Karali MD, Dimopoulos MA. Systemic chemotherapy in inoperable or metastatic bladder cancer. Ann Oncol. 2006;17(4):553-561.
    53. Galsky MD, Pal SK, Lin SW, et al. Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States. Bladder Cancer. 2018;4(2):227-238.
    54. Laurent M, Brureau L, Demery ME, et al. Early chemotherapy discontinuation and mortality in older patients with metastatic bladder cancer: The AGEVIM multicenter cohort study. Urol Oncol. 2017;35(1):34 e39-34 e16.
    55. Li R, Metcalfe M, Kukreja J, Navai N. Role of Radical Cystectomy in Non-Organ Confined Bladder Cancer: A Systematic Review. Bladder Cancer. 2018;4(1):31-40.
    56. Abe T, Matsumoto R, Shinohara N. Role of surgical consolidation in metastatic urothelial carcinoma. Curr Opin Urol. 2016;26(6):573-580.
    57. Hasebe K, Naiki T, Oda R, et al. Long-term survival of a patient with pulmonary metastatic urothelial carcinoma following metastasectomy. Urol Case Rep. 2018;21:52-55.
    58. Faltas BM, Gennarelli RL, Elkin E, Nguyen DP, Hu J, Tagawa ST. Metastasectomy in older adults with urothelial carcinoma: Population-based analysis of use and outcomes. Urol Oncol. 2018;36(1):9 e11-19 e17.
    59. Patel V, Collazo Lorduy A, Stern A, et al. Survival after Metastasectomy for Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis. Bladder Cancer. 2017;3(2):121-132.
    60. Del Bene G, Sternberg CN. Systemic chemotherapy in muscle invasive and metastatic bladder cancer: present and future. Urologia. 2017;84(3):130-141.
    61. Alfred Witjes J, Lebret T, Comperat EM, et al. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur Urol. 2017;71(3):462-475.
    62. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
    63. Powles T, O'Donnell PH, Massard C, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017;3(9):e172411.
    64. Thoma C. Bladder cancer: Activity and safety of avelumab in JAVELIN. Nat Rev Urol. 2018;15(3):137.
    65. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026.
    66. Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
    67. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.
    68. Powles T, Duran I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
    Published April 16, 2019
  • APOBEC Mutagenesis is Associated with FGFR3 S249C Mutations in Bladder Cancer - Expert Commentary

    FGFR3 mutations are common in urothelial carcinoma. The APOBEC mutational process is the dominant mutational mechanism in bladder cancer. The relationship between the overexpression of FGFR3 S249C mutation and APOBEC mutagenesis is not well understood. A new study published by Shi et al. in European Urology examined the link between the APOBEC mutational load and different FGFR3 recurrent mutations in bladder cancer.
    Published August 16, 2019
  • ARID1A Mutation plus CXCL13 Expression Act as Combinatorial Biomarkers to Predict Responses to Immune Checkpoint Therapy in Metastatic Urothelial Carcinoma - Expert Commentary

    The introduction of immune checkpoint inhibitors (ICIs) has improved the outcomes for a subset of metastatic urothelial carcinoma (mUCC) patients. There is a need for a predictive tool to identify those who will benefit from these treatments. A recent study published by Goswami et al. in Science Translational Medicine assessed the use of biomarkers as a predictive tool for response to ICIs in music patients.
    Published September 1, 2020
  • ASCO 2019: A Phase II Study of RC48-ADC in HER2-Positive Patients with Locally Advanced or Metastatic Urothelial Carcinoma - Medical Oncologist Perspective

    Chicago, IL (UroToday.com) Antibody-drug conjugates (ADCs) have made significant progress in several tumor types over the past few years, including brentuximab vedotin for Hodgkin lymphoma, TDM1 for breast cancer, and inotuzumab ozogamicin for non-Hodgkin lymphoma.1 Linking a targeted monoclonal antibody to a drug allows for increased specificity of drug delivery, potentially sparing normal tissue from toxicity and optimizing drug release strategies by forcing intracellular accumulation of released drug in antigen-positive cells.1  
    Published June 3, 2019
  • ASCO 2019: EV-201: Results of Enfortumab Vedotin Monotherapy for Locally Advanced or Metastatic Urothelial Cancer Previously Treated with Platinum and Immune Checkpoint Inhibitors - Medical Oncologist Perspective

    Chicago, IL (UroToday.com) After cisplatin-based chemotherapy and immune checkpoint inhibitors, there exist a paucity of effective therapies for patients with metastatic urothelial carcinoma (mUC). Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) which delivers a microtubule-disrupting agent to tumors expressing Nectin-4, a protein overexpressed in urothelial, breast, pancreatic, lung, and esophageal cancer.1
    Published June 4, 2019
  • ASCO 2019: FIERCE-22: Clinical Activity of Vofatamab - FGFR3 Selective Inhibitor in Combination with Pembrolizumab in WT Metastatic Urothelial Carcinoma - Medical Oncologist Perspective

    Chicago, IL (UroToday.com) FGF receptor 3 (FGFR3) alterations are frequently encountered in urothelial carcinoma, both in non-muscle invasive and muscle-invasive disease.1 For patients with muscle-invasive disease, FGFR3 mutations have been observed in 2% of primary tumors and 9% of metastases.2 FGFR inhibitors have been under evaluation for many years and recently, the FDA granted accelerated approval for erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations who have progressed during or following platinum-containing chemotherapy.

    Published June 4, 2019
  • ASCO 2019: Phase II Study of Nivolumab and Ipilimumab for Advanced Bladder Cancer of Variant Histologies - Medical Oncologist Perspective

    Chicago, IL (UroToday.com) Combination ipilimumab/nivolumab (ipi/nivo) has seen success in melanoma, MSI high colorectal cancer, and renal cell carcinoma (RCC).1 In urothelial carcinoma, CheckMate 032 evaluated the efficacy of ipi/nivo in an open-label, multicenter, phase I/II study where ipi/nivo was given at two different dose cohorts (Ipi-1/Nivo-3, and Ipi-3/Nivo-1). Patients were eligible if they had progressed on one or more prior lines of platinum-based chemotherapy and the primary endpoint was objective response rate by RECIST 1.1. Twenty-six patients received Nivo-1/Ipi-3 and 104 patients received Nivo-3/Ipi-1 and the objective response rate was 38.5% in the Nivo-1/Ipi-3 arm and Nivo-3/Ipi-1 arm.  
    Published June 3, 2019
  • ASCO 2021: Conundrums in First-Line Urothelial Carcinoma: Is More Always Better?

    (UroToday.com) The 2021 American Society of Clinical Oncology (ASCO) annual meeting’s urothelial carcinoma oral abstract session featured a discussant presentation by Dr. Shilpa Gupta discussing conundrums in first-line urothelial carcinoma.
    Published June 10, 2021
  • ASCO 2021: Novel Immunotherapy Approaches Across the Spectrum of Urothelial Cancer Stages

    (UroToday.com) The bladder cancer poster discussion session at American Society of Clinical Oncology (ASCO) 2021 featured a discussant presentation by Dr. Bishoy Faltas examining novel immunotherapy approaches across the spectrum of urothelial cancer stages.

    Published June 5, 2021
  • ASCO 2022: Cabozantinib in Combination with Atezolizumab in Urothelial Carcinoma: Results from Cohorts 3, 4, 5 of the COSMIC-021 Study

    (UroToday.com) The 2022 ASCO annual meeting featured an oral abstract session on kidney and bladder cancer, including a presentation by Dr. Monty Pal discussing results of cohorts 3, 4, and 5 in the COSMIC-021 study assessing cabozantinib + atezolizumab in urothelial carcinoma. Cabozantinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors. Atezolizumab is approved as monotherapy for cisplatin ineligible and PD-L1 positive or platinum-containing chemotherapy-ineligible locally advanced or metastatic urothelial carcinoma. As such, COSMIC-021, a multicenter phase 1b study, is evaluating cabozantinib + atezolizumab (anti‒PD-L1 therapy) in various solid tumors (NCT03170960). Cabozantinib + atezolizumab demonstrated encouraging clinical activity in cohort 2 of COSMIC-021 in patients with urothelial carcinoma previously treated with platinum-containing chemotherapy (presented by Pal S et al., ASCO 2020). Outcomes of cabozantinib + atezolizumab from three other urothelial carcinoma cohorts (C3, C4, C5) were presented at ASCO 2022 by Dr. Pal.

    Published June 3, 2022
  • ASCO 2022: Long-Term Outcomes in EV-301: 24-Month Findings From the Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy in Patients With Previously Treated Advanced Urothelial Carcinoma

    (UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster discussion session focused on Kidney and Bladder cancers on Saturday evening included a presentation from Dr. Jonathan E. Rosenberg examining long-term outcomes of enfortumab vedotin (EV) in patients with previously treated advanced urothelial carcinoma (UC) in the EV-301 trial.

    Published June 4, 2022
  • ASCO 2022: Long-Term Outcomes in Patients with Advanced Urothelial Carcinoma (UC) Who Received Avelumab First-Line Maintenance with or Without Second-Line Treatment: Exploratory Analyses from JAVELIN Bladder 100

    (UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Kidney and Bladder cancers on Saturday afternoon included a presentation from Dr. Joaquim Bellmunt examining long-term outcomes from the JAVELIN Bladder 100 trial among patients receiving first-line avelumab maintenance therapy, with a specific focus on the use of subsequent second-line therapy.

    Published June 4, 2022
  • ASCO 2022: Perioperative Chemoimmunotherapy With Durvalumab for Operable Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single Arm Phase II Trial SAKK 06/17

    (UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster discussion session focused on Kidney and Bladder cancers on Saturday evening included a presentation from Dr. Richard Cathomas discussing the role of peri-operative chemoimmunotherapy for patients undergoing radical cystectomy for muscle invasive urothelial carcinoma based on the SAKK 06/17 trial.

    Published June 4, 2022
  • ASCO 2022: Results From Cohorts 3, 4, 5 of the COSMIC-021 Study - Cabozantinib in Combination With Atezolizumab in Urothelial Carcinoma

    (UroToday.com) Cabozantinib is a tyrosine kinase inhibitor against MET, AXL, and VEGFR that is hypothesized to enhance responses to immune checkpoint inhibitors and is approved in combination with the anti-PD-1 agent nivolumab as first line therapy for advanced renal cell carcinoma. COSMIC-021 (NCT03170960) is a multi-malignancy, multi-arm, and multicenter trial evaluating the efficacy of cabozantinib in combination with the anti-PD-L1 agent atezolizumab. Atezolizumab is a monotherapy treatment option in the first line for advanced urothelial cancers in patients felt to be ineligible for platinum-based chemotherapy. At ASCO 2020, Dr. Pal presented data from cohort 2 of this study, which tested the overall response rate of this combination in advanced urothelial cancers that had progressed on or after platinum-based first line therapy. Of the 30 patients in that cohort, there was a 27% overall response rate with two complete responses, and the median progression-free survival was 5.4 months.

    Published June 4, 2022
  • ASCO GU 2020: New Standards in First-Line Therapy for Advanced Disease

    San Francisco, California (UroToday.com) To close the session entitled “Risk stratification and management of high-risk muscle invasive urothelial carcinoma,” Cora N. Sternberg, MD, provided a clarifying overview of the rapidly advancing landscape of treatments for muscle invasive urothelial carcinoma.  She led by providing perspective on the history of treating metastatic urothelial carcinoma (UC), emphasizing that recent increases in treatment options are dramatic. 
    Published February 15, 2020
  • ASCO GU 2020: Options for Bacillus Calmette-Guérin (BCG) Refractory Disease

    San Francisco, California (UroToday.com) Treatment of patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) remains a significant clinical challenge.
    Published February 15, 2020
  • ASCO GU 2020: Study EV-103: Preliminary Durability Results of Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

    San Francisco, CA (UroToday.com) There are limited effective treatments for patients with metastatic bladder cancer who are platinum ineligible. Single-agent immunotherapy has limited efficacy in an unselected population, with objective response rates (ORRs) in the 10-20% range. Thus, there is an unmet need for our patients with metastatic bladder cancer.

    Published February 14, 2020
  • ASCO GU 2021: Avelumab First-Line Maintenance Plus Best Supportive Care vs Best Supportive Care Alone For Advanced Urothelial Carcinoma: JAVELIN Bladder 100 Subgroup Analysis Based On Duration And Cycles Of First-Line Chemotherapy

    (UroToday.com) Avelumab first-line maintenance therapy is approved in the United States for patients with advanced urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy based on significantly prolonged overall survival versus best supportive care alone (median 21.4 months versus 14.3 months; HR 0.69, 95% CI 0.56-0.86) as reported in the phase III JAVELIN Bladder 100 trial (NCT02603432).1 However, the optimal duration of first-line chemotherapy is unknown and some patients are unable to receive six cycles. At the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Yohann Loriot and colleagues presented results of their post hoc analysis of the JAVELIN Bladder 100 trial, specifically efficacy by duration or number of cycles of first-line chemotherapy.

    Published February 14, 2021
  • ASCO GU 2021: Enfortumab Vedotin in Previously Treated Urothelial Cancer - Results of EV-301 & EV-201 Cohort 2 Discussion

    (UroToday.com) In this presentation, Arlene O. Siefker-Radtke, MD from the University of Texas MD Anderson Cancer Center provided a discussion on two presentations on Enfortumab Vedotin (EV)  in previously treated urothelial cancer. She first reviewed the results of EV-301 (Abstract 393) which provided level 1 evidence of overall survival benefit with EV compared to single-agent chemotherapy in patients who progressed on platinum chemotherapy and immune checkpoint blockade. The trial schema and relevant overall survival data are re-shown below. EV also demonstrated a progression-free survival benefit and improved overall response rates to 41% from 18% with single-agent chemotherapy.
    Published February 17, 2021
  • ASCO GU 2021: First Results from the Phase 3 CheckMate 274 Trial of Adjuvant Nivolumab vs Placebo in Patients Who Underwent Radical Surgery for High-Risk Muscle-Invasive Urothelial Carcinoma

    (UroToday.com) For patients with muscle-invasive bladder cancer who are eligible for curative-intent treatment, cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is a standard of care with improved pathologic response and overall survival (OS) compared to RC alone. Consolidation with chemoradiotherapy (CRT) is an alternative to RC. However, many patients are cisplatin-ineligible and thus often do not receive NAC. In patients who do not receive NAC for whatever reason, there is no conclusive data to support the use of adjuvant therapy. Further, the role of adjuvant chemotherapy is unclear in patients who have residual disease following NAC. In a plenary presentation in the Navigating Uncertain Times in Muscle-Invasive and Advanced Bladder Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Dean Bajorin presents the results of CheckMate-274 assessing the role of adjuvant nivolumab in patients following radical resection with or without NAC with cisplatin.
    Published February 18, 2021
  • ASCO GU 2021: Primary Results of EV-301: A Phase III Trial of Enfortumab Vedotin Versus Chemotherapy in Patients with Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma

    (UroToday.com) Cisplatin chemotherapy is the standard of care for medically fit patients in advanced urothelial carcinoma. Up to 50% of these patients are medically ineligible for cisplatin due to low performance status, renal dysfunction, or other medical comorbidities.  Immune checkpoint blockade is a first line therapeutic option in either platinum ineligible patients or carboplatin eligible patients whose tumors also express PD-L1. Patients who are ineligible for cisplatin and progress on immune checkpoint blockade have limited treatment options, and many efforts are underway to expand the therapeutic armamentarium for this disease context.

    Published February 13, 2021
  • ASCO GU 2021: SURE: An Open Label, Sequential-Arm, Phase II Study of Neoadjuvant Sacituzumab Govitecan, and Sacituzumab Govitecan plus Pembro Before Radical Cystectomy, for Patients with MIBC Who Cannot Receive or Refuse Cisplatin-Based Chemotherapy

    (UroToday.com) Muscle-invasive bladder cancer is a systemic disease as >40% of patients ultimately develop recurrence after radical cystectomy. For patients who cannot receive or refuse cisplatin-based chemotherapy, there is no standard-of-care neoadjuvant therapy. Single-agent pembrolizumab, given in the neoadjuvant setting in patients with T2-4N0M0 muscle-invasive bladder cancer, documented a 42% pathologic complete response-rate (ypT0N0) in the previously published PURE-01 trial.1 However, there is a huge proportion of patients who do not benefit from single-agent immune-checkpoint inhibitors. Sacituzumab govitecan is an antibody-drug conjugate composed of a humanized anti-Trop-2 antibody, SN-38 payload (a parent compound of irinotecan), and a hydrolysable linker for SN-38 release. Based on preliminary data from the TROPHY-U-01 trial, sacituzumab govitecan got fast-track designation for urothelial carcinoma by the US FDA. At the 2021 GU ASCO annual meeting, Dr. Andrea Necchi presented the trial design for the SURE trial, aiming to evaluate the efficacy of neoadjuvant sacituzumab govitecan either as a single-agent (SURE-01) or combined with pembrolizumab (SURE-02) before radical cystectomy.
    Published February 13, 2021
  • ASCO GU 2021: TROPiCS-04: Study of Sacituzumab Govitecan in Metastatic Or Locally Advanced Unresectable Urothelial Cancer That Has Progressed After Platinum and Checkpoint Inhibitor Therapy

    (UroToday.com) While cisplatin-based chemotherapy is an accepted first-line treatment for patients with advanced or metastatic urothelial carcinoma and immune checkpoint inhibitors (CPI) are used in both the first-line setting for patients who are cisplatin-ineligible and as maintenance or second-line therapy in those who have previously received cisplatin-based chemotherapy, there are limited treatment options past these. Recently, sacituzumab govitecan, an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase I inhibitor), has been utilized in this population.
    Published February 12, 2021
  • ASCO GU 2022: A Randomized, Double Blind, Biomarker Selected, Phase II Clinical Trial of Maintenance PARP Inhibition Following Chemotherapy for Metastatic Urothelial Carcinoma: Final Analysis of the ATLANTIS Rucaparib Arm

    (UroToday.com) In an oral abstract presentation on the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focussed on urothelial carcinoma, Dr. Crabb presented results of the rucaparib arm of the ATLANTIS trial among patients with metastatic urothelial carcinoma (mUC). Among patients with mUC, a subset of approximately 25%have a DNA repair deficiency (DRD) phenotype which is associated with response to platinum-based chemotherapy (PBC). Given this mechanism of effect, the authors postulated that switch maintenance with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib would improve outcomes for patients who had derived benefit from PBC.

    Published February 19, 2022
  • ASCO GU 2022: Analysis of Disease-Free Survival in CheckMate 274 by PD-L1 Combined Positive Score and Tumor Proportion Score

    (UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma, in Poster Session B, Dr. Galsky presented an analysis of the CheckMate274 trial of adjuvant nivolumab in urothelial carcinoma. In the primary publication of the trial, adjuvant nivolumab improved disease-free survival (DFS) with both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and among patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). However, an exploratory subgroup analysis showed a trend toward a DFS benefit with nivolumab in patients with TPS < 1% (0.82; 95% CI, 0.63–1.06).

    Published February 18, 2022
  • ASCO GU 2022: BAYOU: A Phase II, Randomized, Multicenter, Double-Blind, Study of Durvalumab in Combination With Olaparib for the First-Line Treatment of Platinum-Ineligible Patients With Unresectable, Stage IV Urothelial Carcinoma

    (UroToday.com) In an oral abstract presentation on the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma, Dr. Rosenberg presented results of BAYOU, examining durvalumab and olaparib as first-line therapy in platinum-ineligible patients with unresectable stage IV urothelial carcinoma.

    Published February 19, 2022
  • ASCO GU 2022: Discussion on the ATLANTIS and BAYOU Trials in Advanced Urothelial Cancer

    (UroToday.com) In an oral abstract presentation on the first day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focussed on prostate cancer, Dr. Srinivas provided a discussion following presentations from Dr. Crabb and Dr. Rosenberg on the ATLANTISand BAYOU trials, respectively.

    Published February 20, 2022
  • ASCO GU 2022: Impact of PD-L1 Expression on Conventional Urothelial Bladder Carcinoma Genomic Alteration Profile

    (UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma, in Poster Session B, Dr. Grivas presented a poster examining the effect of PD-L1 expression, as determined by immunohistochemistry (IHC), on genomic alteration profiles in patients with urothelial bladder carcinoma (UBC).

    Published February 18, 2022
  • ASCO GU 2022: Meet-URO12 Phase II Study of Niraparib Plus Best Supportive Care vs BSC Alone As Maintenance Treatment in Advanced Urothelial Carcinoma Patients Whose Disease Did Not Progress After First-Line Platinum-Based Chemotherapy

    (UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma, in Poster Session B, Dr. Vignani presented results of the Meet-URO12 trial examining niraparib as maintenance therapy in advanced urothelial carcinoma (UC). Niraparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) enzymes. Platinum-based chemotherapy is the accepted standard of care in first line treatment of advanced UC. Thus, based on the association of mutations in homologous recombination repair (HRR) genes with platinum sensitivity, the authors hypothesized that maintenance treatment with niraparib would improve outcomes among patients who have an objective response (OR) or stable disease (SD) to first line chemotherapy.

    Published February 18, 2022
  • ASCO GU 2022: Primary Analysis From DS8201-a-U105: A Phase 1b, 2-Part, Open-Label Study of Trastuzumab Deruxtecan (T-DXd) With Nivolumab in Patients With HER2-Expressing Urothelial Carcinoma

    (UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022, the Rapid Abstract Session highlighted key abstract in urothelial carcinoma, including work by Dr. Galsky and colleagues who presented results of the DS8201-A-U105 trial of trastuzumab deruxtecan (T-DXd) with nivolumab in patients with HER2-expressing urothelial carcinoma (UC). Dating back almost two decades, HER2 overexpression was found in invasive UC, suggesting a role for HER2 in disease progression and prognosis. T-DXd is an antibody-drug conjugate (ADC) comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. In preclinical models, T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone. Thus, the authors performed a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572).

    Published February 18, 2022
  • ASCO GU 2022: Study EV-302: A Two-Arm, Open-Label, Randomized Controlled Phase 3 Study of Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy in Previously Untreated Advanced Urothelial Carcinoma

    (UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma during the Trials in Progress Poster Session B, Dr. Van Der Heijden presented the rationale and design of EV-302 assessing enfortumab vedotin (EV) with pembrolizumab compared to chemotherapy as first-line treatment in advanced urothelial carcinoma (aUC).

    Published February 20, 2022
  • ASTRO 2021: Controversies in the Management of Muscle-Invasive Bladder Cancer

    (UroToday.com) In the Latin America ASTRO session of the American Society for Radiation Oncology (ASTRO) Annual Congress, Dr. Berlin presented on controversies in the management of patients with Muscle-invasive bladder cancer (MIBC). He began by highlighting that this is an exciting topic, over the last 10 to 15 years. Previously, he highlighted a self-perpetuating issue of limited research funding leading to a poor understanding of disease biology, an absence of novel therapeutic approaches, and a lack of public awareness and engagement which would in turn feed limited research funding. However, more recently, there was been substantial progress in this disease space ranging from neoadjuvant therapy (including single-agent immune checkpoint inhibitors, immune checkpoint inhibitor combinations, and combination chemo-immunotherapy), adjuvant systemic therapy, and advances in bladder sparing treatment approaches.

    Published October 29, 2021
  • AUA 2021: State-of-the-art Lecture: First and Second Line Therapy in Advanced and Metastatic Bladder Cancer: A Changing Paradigm

    (UroToday.com) In this rapid review for the American Urologic Association (AUA) plenary session, Dr. Cora Sternberg summarized the current status of first and second-line therapy for advanced and metastatic urothelial cancer – while also touching on changes that are upcoming.
    Published September 10, 2021
  • Avelumab, an Anti–Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study - Expert Commentary

    Platinum-resistant urothelial carcinoma is a lethal disease. After a long period of therapeutic stagnation, the last two years have witnessed an explosion in the development of new second-line therapies.
    Published August 10, 2017
  • Biomarkers, Immunotherapy and Future Directions

    (UroToday.com) In anticipation of the 2021 American Urological Association (AUA) Annual Meeting which is being held, in a delayed fashion, in September, the AUA hosted a “May Kick-Off Weekend” which highlighted a variety of important topics in both benign urology and urologic oncology. Saturday afternoon, Adam Feldman led a course entitled “Trimodality Therapy (TMT) for Management of Muscle Invasive Bladder Cancer” along with faculty Richard Lee and Jason Efstathiou.

    Published May 23, 2021
  • Comparing the Outcomes of ddMVAC vs. GC before Cystectomy in Patients with Muscle Invasive Bladder Cancer - Expert Commentary

    Patients with muscle-invasive bladder cancer  (MIBC) who are treated with neoadjuvant chemotherapy (NAC) before cystectomy have a survival advantage. Few studies comparing cancer control and survival outcomes for different NAC regimens exist.
    Published October 26, 2018
  • Do Molecular Subtypes of Muscle-invasive Bladder Cancer Predict Response to Neoadjuvant Chemotherapy? - Expert Commentary

    Neoadjuvant chemotherapy is a standard of care for muscle-invasive bladder cancer (MIBC). Recently, new molecular subtypes based on gene-expression were identified but their impact on response to neoadjuvant has been unclear.
    Published April 21, 2017
  • Does Pathologic Response to Neoadjuvant Chemotherapy Predict Survival in Muscle-Invasive Bladder Cancer Patients? - Expert Commentary

    Patients who achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have a better prognosis compared to patients with pathologic residual disease (pRD). The clinical value of these pathological responses over the long-term to NAC is not well understood.

    A new article published by Waingankar et al. in Urologic Oncology: Seminars and Original Investigations1examined the impact of NAC pathological response on the anticipated survival (conditional survival) based on the years from the RC. Using the National Cancer Database, the investigators identified patients diagnosed with localized MIBC and treated with NAC and RC between 1998 and 2012. They included 1,533 patients in the study. Of these, 314 patients achieved pCR (pathologic stage of Ta, Tis, or T0 and N0) and 1,239 had pRD patients (≥ pT1 disease and/or ≥pN1). They used Kaplan-Meier analysis to calculate the survival between the two groups and used a Cox proportional hazard model to study the effect of achieving pCR on survival from the time of RC.

    During the follow-up period, Patients with pCR had a significantly higher initial probability of survival in year zero (P < 0.001). This effect was sustained in subsequent years. Patients with pCR had improved overall survival relative to those with pRD. As expected, the prognosis for MIBC patients continued to improve with ongoing survivorship, both for patients with pCR and pRD following NAC and RC.

    This study adds to the growing literature examining the pCR after NAC as a predictor of overall survival. However, several pathologic and clinical factors affect the accuracy of pCR assessment. Testing this concept in prospective clinical trials is needed to validate pCR as an endpoint for future clinical trials.

    Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

    Reference: 
    1. Waingankar, Nikhil, Rachel Jia, Kathryn E. Marqueen, Francois Audenet, John P. Sfakianos, Reza Mehrazin, Bart S. Ferket, Madhu Mazumdar, and Matthew D. Galsky. "The impact of pathologic response to neoadjuvant chemotherapy on conditional survival among patients with muscle-invasive bladder cancer." In Urologic Oncology: Seminars and Original Investigations. Elsevier, 2019.

    Read the Abstract
    Published September 9, 2019
  • EAU 2020: Novel Urothelial Cancer Treatment Beyond PD-1/PD-L1 Inhibition

    (UroToday.com) Outcomes of immunotherapy have been the highlight of meetings over the last decade. At the 2020 European Association of Urology (EAU) Virtual Meeting, Yohann Loriot, MD, PhD, discussed novel treatment options beyond immunotherapy. As noted by Dr. Loriot, the vast majority of trials with new drugs are investigating immunotherapy, but a better understanding of the tumor biology is identifying new targets. Currently, fibroblast growth factor receptors (FGFR) inhibitors and antibody-drug conjugates are the best approaches, and as such precision-medicine should be implemented. In muscle invasive bladder cancer, several genetic alterations are potentially targetable, including FGFR3, HHRm, HER2, components of angiogenesis, and the epigenome.
    Published July 19, 2020
  • EAU 2021: Circulating Tumor Cell-Driven Use of Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer: Final Results of the CirGuidance Study

    (UroToday.com) The first talk of this game-changing session at the 2021 European Association of Urology (EAU) annual meeting, Dr. Nick Beije of Rotterdam, presented the final results of the CirGuidance Study, which focused on the use of the circulating tumor cells (CTCs) to drive neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). This was followed by a discussion and summary from Dr. Morgan Roupret.
    Published July 11, 2021
  • EAU 2021: Predictive Markers for Response in Urothelial Cancer: Are We There Yet?

    (UroToday.com) In this presentation during the thematic session at the 2021 European Association of Urology (EAU) annual meeting, focusing on immunotherapy in urothelial cancer, Dr. Thomas Powles reviews predictive markers for response in urothelial cancer. 
    Published July 12, 2021
  • Efficacy and Safety of Neoadjuvant Pembrolizumab in Patients with Muscle-Invasive Bladder Cancer - Expert Commentary

    Neoadjuvant chemotherapy followed by radical cystectomy (RC) with lymph node dissection is the standard of care in patients with muscle-invasive urothelial bladder carcinoma (MIBC). Unfortunately, many patients are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy.
    Published March 6, 2019
  • EMUC 2020: Neoadjuvant Versus Adjuvant Strategies in Locally Advanced Bladder Cancer

    (UroToday.com) In an oral presentation in a session examining neoadjuvant versus adjuvant strategies in locally advanced bladder cancer at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Andrea Necchi led a discussion of neoadjuvant strategies in advanced bladder cancer.
    Published November 15, 2020
  • EMUC 2020: Optimal First Line Therapy in Metastatic Bladder Cancer Disease

    (UroToday.com) In an oral presentation in the Refining the Treatment of Bladder Cancer session at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Matthew Glasky presented an overview of optimal first-line approaches to the treatment of metastatic bladder cancer.
    Published November 14, 2020
  • Erdafitinib PI

    HIGHLIGHTS OF PRESCRIBING INFORMATION


    These highlights do not include all the information needed to use BALVERSATMsafely and effectively. See full prescribing information for BALVERSA.

    BALVERSA (erdafitinib) tablets, for oral use Initial U.S. Approval: 2019

    ---------------------------------INDICATIONS AND USAGE--------------------------------

    BALVERSA is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has

    • susceptible FGFR3 or FGFR2 genetic alterations and
    • progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
    Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA. (1, 2.1)

    This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1, 14)

    -----------------------------DOSAGE AND ADMINISTRATION-----------------------------

    • Confirm the presence of FGFR genetic alterations in tumor specimens prior to initiation of treatment with BALVERSA. (2.1)
    • Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. (2.2)
    • Swallow whole with or without food. (2.2)
    ----------------------------DOSAGE FORMS AND STRENGTHS---------------------------

    Tablets: 3 mg, 4 mg, and 5 mg. (3)

    -----------------------------------CONTRAINDICATIONS------------------------------------

    None. (4)

    -----------------------------WARNINGS AND PRECAUTIONS-----------------------------

    • Ocular disorders: BALVERSA can cause central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED). Perform monthly ophthalmological examinations during the first four months of treatment, every 3 months afterwards, and at any time for visual symptoms. Withhold BALVERSA when CSR/RPED occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. (2.3, 5.1)
    • Hyperphosphatemia: Increases in phosphate levels are a pharmacodynamic effect of BALVERSA. Monitor for hyperphosphatemia and manage with dose modifications when required. (2.3, 5.2)
    • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception (5.3, 8.1, 8.3).

    BALVERSATM(erdafitinib) tablets

    -----------------------------------ADVERSE REACTIONS------------------------------------

    The most common adverse reactions including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP.at 1-800-526-7736 (1-800-JANSSEN and www.BALVERSA.com) or FDA at

    1-800-FDA-1088 orwww.fda.gov/medwatch.

    ------------------------------------DRUG INTERACTIONS-----------------------------------

    • Strong CYP2C9 or CYP3A4 inhibitors: Consider alternative agents or monitor closely for adverse reactions. (7.1)
    • Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. (7.1)
    • Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg. (7.1)
    • Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. (2.3, 7.1)
    • CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. (7.2)
    • OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. (7.2)
    • P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2)
    ------------------------------USE IN SPECIFIC POPULATIONS-----------------------------

    • Lactation: Advise not to breastfeed. (8.2)
    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 04/2019

    FULL PRESCRIBING INFORMATION: CONTENTS*

    1. INDICATIONS AND USAGE
    2. DOSAGE AND ADMINISTRATION
      1. Patient Selection
      2. Recommended Dosage and Schedule
      3. Dose Modifications for Adverse Reactions
    3. DOSAGE FORMS AND STRENGTHS
    4. CONTRAINDICATIONS
    5. WARNINGS AND PRECAUTIONS
      1. Ocular Disorders
      2. Hyperphosphatemia
      3. Embryo-Fetal Toxicity
    6. ADVERSE REACTIONS
      1. Clinical Trials Experience
    7. DRUG INTERACTIONS
      1. Effect of Other Drugs on BALVERSA
      2. Effect of BALVERSA on Other Drugs
    8. USE IN SPECIFIC POPULATIONS
      1. Pregnancy
      2. Lactation
      3. Females and Males of Reproductive Potential
      4. Pediatric Use
      5. Geriatric Use
      6. CYP2C9 Poor Metabolizers
    9. DESCRIPTION
    10. CLINICAL PHARMACOLOGY
      1. 12.1.Mechanism of Action
      2. 12.2.Pharmacodynamics
      3. 12.3.Pharmacokinetics
      4. 12.5 Pharmacogenomics
    11. NONCLINICAL TOXICOLOGY
      1. 13.1.Carcinogenesis, Mutagenesis, and Impairment of Fertility
    12. CLINICAL STUDIES
      1. 14.1.Urothelial Carcinoma with Susceptible FGFR Genetic Alterations
    13. HOW SUPPLIED/STORAGE AND HANDLING
    14. PATIENTCOUNSELING INFORMATION
    *Sections or subsections omitted from the full prescribing information are not listed.

    FULL PRESCRIBING INFORMATION

    1. INDICATIONS AND USAGE
    BALVERSATM is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC), that has:

    • susceptible FGFR3 or FGFR2 genetic alterations, and
    • progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum- containing chemotherapy.
    Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA [seeDosage andAdministration(2.1)andClinicalStudies (14)].

    This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [seeClinicalStudies(14)].

    1. DOSAGE AND ADMINISTRATION
      1. 2.1.Patient Selection
    Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic [seeClinicalStudies(14.1)].

    Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics.

    1. 2.2.Recommended Dosage and Schedule
    The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate (PO4) levels and tolerability at 14 to 21 days [seeDosageandAdministration(2.3)].

    Swallow tablets whole with or without food. If vomiting occurs any time after taking BALVERSA, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

    If a dose of BALVERSA is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose.

    Dose Increase based on Serum Phosphate Levels

    Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia [seePharmacodynamics(12.2)].

    1. 2.3.Dose Modifications for Adverse Reactions
    The recommended dose modifications for adverse reactions are listed in Table 1.

    Table 1: BALVERSA Dose Reduction Schedule




    Dose

    1stdose reduction

    2nddose reduction

    3rddose reduction

    4thdose reduction

    5thdose reduction

    9 mg

    (three 3 mg tablets)

    8 mg

    (two 4 mg tablets)

    6 mg

    (two 3 mg tablets)

    5 mg

    (one 5 mg tablet)

    4 mg

    (one 4 mg tablet)




    Stop




    8 mg

    (two 4 mg tablets)

    6 mg

    (two 3 mg tablets)

    5 mg

    (one 5 mg tablet)

    4 mg

    (one 4 mg tablet)




    Stop







    Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.

    Table 2: Dose Modifications for Adverse Reactions




    Adverse Reaction

    BALVERSA Dose Modification

    Hyperphosphatemia

    In all patients, restrict phosphate intake to 600-800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to < 5.5 mg/dL.

    5.6-6.9 mg/dL (1.8-2.3 mmol/L)

    Continue BALVERSA at current dose.

    7.0-9.0 mg/dL (2.3-2.9 mmol/L)

    Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then restart BALVERSA at the same dose level. A dose reduction may be implemented for hyperphosphatemia lasting

    > 1 week.

    > 9.0 mg/dL (> 2.9 mmol/L)

    Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 1 dose level lower.

    > 10.0 mg/dL (> 3.2 mmol/L) or significant alteration in baseline renal function or Grade 3 hypercalcemia

    Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 2 dose levels lower.

    Central Serous Retinopathy/Retinal Pigment Epithelial Detachment (CSR/RPED)

    Grade 1: Asymptomatic; clinical or diagnostic observations only

    Withhold until resolution. If resolves within

    4 weeks, resume at the next lower dose level. Then, if no recurrence for a month, consider re-escalation. If stable for 2 consecutive eye exams but not resolved, resume at the next lower dose level.

    Grade 2: Visual acuity 20/40 or better or ≤ 3 lines of decreased vision from baseline

    Withhold until resolution. If resolves within 4 weeks, may resume at the next lower dose level.

    Grade 3: Visual acuity worse than 20/40 or > 3 lines of decreased vision from baseline

    Withhold until resolution. If resolves within 4 weeks, may resume two dose levels lower.

    If recurs, consider permanent discontinuation.

    Grade 4: Visual acuity 20/200 or worse in affected eye

    Permanently discontinue.

    Other Adverse Reactionsa

    Grade 3

    Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower.

    Grade 4

    Permanently discontinue.

    a Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv4.03).

    1. DOSAGE FORMS AND STRENGTHS
    Tablets:

    • 3 mg: Yellow, round biconvex, film-coated, debossed with “3” on one side; and “EF” on the other side.
    • 4 mg: Orange, round biconvex, film-coated, debossed with “4” on one side; and “EF” on the other side.
    • 5 mg: Brown, round biconvex, film-coated, debossed with “5” on one side; and “EF” on the other side.
    1. CONTRAINDICATIONS
    None.

    1. WARNINGS AND PRECAUTIONS
      1. 5.1.Ocular Disorders
    BALVERSA can cause ocular disorders, including central serous retinopathy/ retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

    CSR/RPED was reported in 25% of patients treated with BALVERSA, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued BALVERSA.

    Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

    Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.

    Withhold BALVERSA when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [seeDosageandAdministration(2.3)].

      1. 5.2.Hyperphosphatemia
    Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)].Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8 –116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA.

    Monitor for hyperphosphatemia and follow the dose modification guidelines when required [see DosageandAdministration2.2,2.3].

      1. 5.3.Embryo-Fetal Toxicity
    Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [seeUseinSpecificPopulations (8.1,8.3) andClinicalPharmacology(12.1)].

    1. ADVERSE REACTIONS
    The following serious adverse reactions are also described elsewhere in the labeling:

    • Ocular Disorders [seeWarningandPrecautions(5.1)].
    • Hyperphosphatemia [seeWarningandPrecautions(5.2)].
      1. 6.1.Clinical Trials Experience
    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    The safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy [seeClinicalStudies(14.1)]. Patients were treated with BALVERSA at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months).

    The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar- plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, palmar-plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia.

    An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.

    Serious adverse reactions occurred in 41% of patients including eye disorders (10%).

    Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).

    Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysaesthesia syndrome (8%).

    Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysaesthesia syndrome (7%),

    paronychia (7%), and nail dystrophy (6%).







    Table 3 presents ARs reported in ≥10% of patients treated with BALVERSA at 8 mg once daily.

    Table 3: Adverse Reactions Reported in 10% (Any Grade) or ≥5% (Grade 3-4) of Patients







    Adverse Reaction

    BALVERSA 8 mg daily (N=87)

    All Grades (%)

    Grade 3-4 (%)

    Any

    100

    67

    Gastrointestinal disorders

    92

    24

    Stomatitis

    56

    9

    Diarrhea

    47

    2

    Dry mouth

    45

    0

    Constipation

    28

    1

    Abdominal paina

    23

    2

    Nausea

    21

    1

    Vomiting

    13

    2

    Metabolism and nutrition disorders

    90

    16

    Decreased appetite

    38

    0

    General disorders and admin. site conditions

    69

    13

    Fatigueb

    54

    10

    Pyrexia

    14

    1

    Skin and subcutaneous disorders

    75

    16

    Onycholysisc

    41

    10

    Dry skind

    34

    0

    Palmar-plantar erythrodysaesthesia

    26

    6

    Alopecia

    26

    0

    Nail discoloration

    11

    0

    Eye disorders

    62

    11

    Dry eyee

    28

    6

    Vision blurred

    17

    0

    Lacrimation increased

    10

    0

    Nervous system disorders

    57

    5

    Dysgeusia

    37

    1

    Infections and infestations

    56

    20

    Paronychia

    17

    3

    Urinary tract infection

    17

    6

    Conjunctivitis

    11

    0

    Respiratory, thoracic and mediastinal disorders

    40

    7

    Oropharyngeal pain

    11

    1

    Dyspneaf

    10

    2

    Renal and urinary tract disorders

    38

    10

    Hematuria

    11

    2

    Musculoskeletal and connective tissue disorders

    31

    0

    Musculoskeletal paing

    20

    0

    Arthralgia

    11

    0

    Investigations

    44

    5

    Weight decreasedh

    16

    0

    a Includes abdominal pain, abdominal discomfort, abdominal pain upper, and abdominal pain lower

    b Includes asthenia, fatigue, lethargy, and malaise

    c Includes onycholysis, onychoclasis, nail disorder, nail dystrophy, and nail ridging

    d Includes dry skin and xerostomia

    e Includes dry eye, xerophthalmia, keratitis, foreign body sensation, and corneal erosion

    f Includes dyspnea and dyspnea exertional

    g Includes back pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal chest pain, neck pain, pain in extremity

    h Includes weight decreased and cachexia

    Table4: Laboratory Abnormalities Reported in ≥ 10% (All Grade) or ≥ 5% (Grade 3-4) of Patients




    Laboratory Abnormality

    BALVERSA 8 mg daily (N=86a)

    All Grades (%)

    Grade 3-4 (%)

    Hematology

    Hemoglobin decreased

    35

    3

    Platelets decreased

    19

    1

    Leukocytes decreased

    17

    0

    Neutrophils decreased

    10

    2

    Chemistry

    Phosphate increased

    76

    1

    Creatinine increased

    52

    5

    Sodium decreased

    40

    16

    Alanine aminotransferase increased

    41

    1

    Alkaline phosphatase increased

    41

    1

    Albumin decreased

    37

    0

    Aspartate aminotransferase increased

    30

    0

    Magnesium decreased

    30

    1

    Phosphate decreased

    24

    9

    Calcium increased

    22

    3

    Potassium increased

    16

    0

    Fasting glucose increased

    10

    0

    a One of the 87 patients had no laboratory tests.

    1. DRUG INTERACTIONS
      1. 7.1.Effect of Other Drugs on BALVERSA
    Table 5 summarizes drug interactions that affect the exposure of BALVERSA or serum phosphate level and their clinical management.




    Strong CYP2C9 or CYP3A4 Inhibitors







    Clinical Impact

    • Co-administration of BALVERSA with strong inhibitors of CYP2C9 or CYP3A4 increased erdafitinib plasma concentrations [see Clinical Pharmacology(12.3)].
    • Increased erdafitinib plasma concentrations may lead to increased drug-related toxicity [see WarningsandPrecautions(5)].









    Clinical Management

    • Consider alternative therapies that are not strong inhibitors of CYP2C9 or CYP3A4 during treatment with BALVERSA.
    • If co-administration of a strong inhibitor of CYP2C9 or CYP3A4 is unavoidable, monitor closely for adverse reactions and consider dose modifications accordingly [seeDosage andAdministration(2.3)]. If the strong inhibitor is discontinued, the BALVERSA dose may be
    increased in the absence of drug-related toxicity.

    Strong CYP2C9 or CYP3A4 Inducers




    Clinical Impact

    • Co-administration of BALVERSA with strong inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations significantly [seeClinicalPharmacology(12.3)].
    • Decreased erdafitinib plasma concentrations may lead to decreased activity.
    Clinical Management

    • Avoid co-administration of strong inducers of CYP2C9 or CYP3A4 with BALVERSA.
    Moderate CYP2C9 or CYP3A4 Inducers




    Clinical Impact

    • Co-administration of BALVERSA with moderate inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations [see Clinical Pharmacology(12.3)].
    • Decreased erdafitinib plasma concentrations may lead to decreased activity.












    Clinical Management

    • If a moderate CYP2C9 or CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA dose as recommended (8 mg once daily with potential to increase to 9 mg once daily based on serum phosphate levels on Days 14 to 21 and tolerability).
    • If a moderate CYP2C9 or CYP3A4 inducer must be co-administered after the initial dose increase period based on serum phosphate levels and tolerability, increase BALVERSA dose up to 9 mg.
    • When a moderate inducer of CYP2C9 or CYP3A4 is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity.
    Table 5: Drug Interactions that Affect BALVERSA

    Table 5: Drug Interactions that Affect BALVERSA (continued)

    Serum Phosphate Level-Altering Agents










    Clinical Impact

    • Co-administration of BALVERSA with other serum phosphate level-altering agents may increase or decrease serum phosphate levels [seePharmacodynamics(12.2)].
    • Changes in serum phosphate levels due to serum phosphate level-altering agents (other than erdafitinib) may interfere with serum phosphate levels needed for the determination of initial dose increased based on serum phosphate levels [see DosageandAdministration(2.3)].



    Clinical Management

    • Avoid co-administration of serum phosphate level-altering agents with BALVERSA before initial dose increase period based on serum phosphate levels (Days 14 to 21) [seeDosageand Administration(2.3)].
      1. 7.2 Effect of BALVERSA on Other Drugs
    Table 6 summarizes the effect of BALVERSA on other drugs and their clinical management.

    Table 6: BALVERSA Drug Interactions that Affect Other Drugs

    CYP3A4 Substrates







    Clinical Impact

    • Co-administration of BALVERSA with CYP3A4 substrates may alter the plasma concentrations of CYP3A4 substrates [see Clinical Pharmacology (12.3)].
    • Altered plasma concentrations of CYP3A4 substrates may lead to loss of activity or increased toxicity of the CYP3A4 substrates.
    Clinical Management

    • Avoid co-administration of BALVERSA with sensitive substrates of CYP3A4 with narrow therapeutic indices.
    OCT2 Substrates







    Clinical Impact

    • Co-administration of BALVERSA with OCT2 substrates may increase the plasma
    concentrations of OCT2 substrates [see Clinical Pharmacology (12.3)].

    • Increased plasma concentrations of OCT2 substrates may lead to increased toxicity of the OCT2 substrates.
    Clinical Management

    • Consider alternative therapies that are not OCT2 substrates or consider reducing the dose of OCT2 substrates (e.g., metformin) based on tolerability.
    P-glycoprotein (P-gp) Substrates







    Clinical Impact

    • Co-administration of BALVERSA with
    P-gp substrates may increase the plasma concentrations of P-gp substrates [seeClinical Pharmacology(12.3)].

    • Increased plasma concentrations of P-gp substrates may lead to increased toxicity of the P-gp substrates.



    Clinical Management

    • If co-administration of BALVERSA with P-gp substrates is unavoidable, separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic index.
    1. USE IN SPECIFIC POPULATIONS
      1. 8.1.Pregnancy
    Risk Summary

    Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman [see ClinicalPharmacology(12.1)]. There are no available data on BALVERSA use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

    Data

    Animal Data

    In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight.

      1. 8.2.Lactation
    Risk Summary

    There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose.

      1. 8.3.Females and Males of Reproductive Potential
    Pregnancy Testing

    Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with BALVERSA.

    Contraception

    Females

    BALVERSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [seeUseinSpecific Population(8.1)].

    Males

    Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [seeUseinSpecificPopulations(8.1)].

    Infertility

    Females

    Based on findings from animal studies, BALVERSA may impair fertility in females of reproductive potential [seeNonclinicalToxicology(13.1)].

      1. 8.4.Pediatric Use
    Safety and effectiveness of BALVERSA in pediatric patients have not been established.

    In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats.

      1. 8.5.Geriatric Use
    Of the 416 patients treated with BALVERSA in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [seeClinicalStudies(14)].

      1. 8.6.CYP2C9 Poor Metabolizers
    CYP2C9*3/*3 Genotype:Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype [see Pharmacogenomics(12.5)].

    1. DESCRIPTION
    Erdafitinib, the active ingredient in BALVERSA, is a kinase inhibitor. The chemical name is N-(3,5-dimethoxyphenyl)-N’-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol- 4-yl)quinoxalin-6-yl]ethane-1,2-diamine. Erdafitinib is a yellow powder. It is practically insoluble, or insoluble to freely soluble in organic solvents, and slightly soluble to practically insoluble, or insoluble in aqueous media over a wide range of pH values. The molecular formula is C 25H30N6O 2 and molecular weight is 446.56. Chemical structure of erdafitinib is as follows:
    Erdafitinib PI

    BALVERSA (erdafitinib) is supplied as 3 mg, 4 mg or 5 mg film-coated tablets for oral administration and contains the following inactive ingredients:

    Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol, Meglumine, and Microcrystalline Cellulose.

    Film Coating: (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcohol-partially hydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red (for the orange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only).

    1. CLINICAL PHARMACOLOGY
      1. 12.1.Mechanism of Action
    Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on invitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

      1. 12.2.Pharmacodynamics
    Cardiac Electrophysiology

    Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e.,

    > 20 ms) on the QTc interval.

    Serum Phosphate

    Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. BALVERSA should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing [seeDosageandAdministration(2.3)].

    In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels [seeDrug Interactions(7.1)].

      1. 12.3.Pharmacokinetics
    Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (C max), area under the curve (AUCtau), and minimum observed plasma concentration (C min) were 1,399 ng/mL (51%), 29,268 ng•h/mL (60%), and 936 ng/mL (65%), respectively.

    Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold.

    Absorption

    Median time to achieve peak plasma concentration (t max) was 2.5 hours (range: 2 to 6 hours).

    Effect of Food

    No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.

    Distribution

    The mean apparent volume of distribution of erdafitinib was 29 L in patients.

    Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein.

    Elimination

    The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. The mean effective half-life of erdafitinib was 59 hours in patients.

    Metabolism

    Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites.

    Excretion

    Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).

    Specific Populations

    No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21-88 years), sex, race, body weight (36-132 kg), mild (eGFR [estimated glomerular filtration rate, using modification of diet in renal disease equation] 60 to 89 mL/min/1.73 m2) or moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0–1.5 x ULN and any AST).

    The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring dialysis, moderate or severe hepatic impairment is unknown.

    Drug Interaction Studies

    Clinical Studies and Model-Based Approaches

    Strong CYP2C9 Inhibitors:

    Erdafitinib mean ratios (90% CI) for Cmax and AUC inf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone.

    Strong CYP3A4 Inhibitors:

    Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone.

    Strong CYP3A4/2C9 Inducers:

    Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib Cmax and AUC.

    In VitroStudies

    CYP Substrates:

    Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.

    Transporters:

    Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2.

    Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations.

    Acid-Lowering Agents:

    Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H 2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.

    12.5 Pharmacogenomics

    CYP2C9 activity is reduced in individuals with genetic variants, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Erdafitinib exposure was similar in subjects with CYP2C9*1/*2 and *1/*3 genotypes relative to subjects with CYP2C9*1/*1 genotype (wild type). No data are available in subjects characterized by other genotypes (e.g., *2/*2, *2/*3, *3/*3). Simulation suggested no clinically meaningful differences in erdafitinib exposure in subjects with CYP2C9*2/*2 and

    *2/*3 genotypes. The exposure of erdafitinib is predicted to be 50% higher in subjects with the CYP2C9*3/*3 genotype, estimated to be present in 0.4% to 3% of the population among various ethnic groups.

    1. NONCLINICAL TOXICOLOGY
      1. 13.1.Carcinogenesis, Mutagenesis, and Impairment of Fertility
    Carcinogenicity studies have not been conducted with erdafitinib.

    Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitromicronucleus or an invivorat bone marrow micronucleus assay.

    Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.

    1. CLINICAL STUDIES
      1. 14.1.Urothelial Carcinoma with Susceptible FGFR Genetic Alterations
    Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma (mUC). Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty- seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as

    determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen ® FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for BALVERSA.

    Patients received a starting dose of BALVERSA at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1.

    The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin- based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy.

    Efficacy results are summarized in Table 7 and Table 8. Overall response rate was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy.

    Table 7: Efficacy Results




    Endpoint

    BIRCaassessment

    N=87

    ORR (95% CI)

    32.2% (22.4, 42.0)

    Complete response (CR)

    2.3%

    Partial response (PR)

    29.9%

    Median DoR in months (95% CI)

    5.4 (4.2, 6.9)

    a BIRC: Blinded Independent Review Committee ORR = CR + PR

    CI = Confidence Interval

    Table 8: Efficacy Results by FGFR Genetic Alteration




    BIRCaassessment

    FGFR3 Point Mutation

    N=64

    ORR (95% CI)

    40.6% (28.6, 52.7)

    FGFR3 Fusion b, c

    N=18

    ORR (95% CI)

    11.1% (0, 25.6)

    FGFR2 Fusion c

    N=6

    ORR

    0

    a BIRC: Blinded Independent Review Committee

    b Both responders had FGFR3-TACC3_V1 fusion

    c One patient with a FGFR2-CASP7/FGFR3-TACC3_V3 fusion is reported in both FGFR2 fusion and FGFR3 fusion above

    ORR = CR + PR

    CI = Confidence Interval

    1. HOW SUPPLIED/STORAGE AND HANDLING
    BALVERSA™ (erdafitinib) tablets are available in the strengths and packages listed below:

    • 3 mg tablets: Yellow, round biconvex, film-coated, debossed with “3” on one side and “EF” on the other side.
    • Bottle of 56-tablets with child resistant closure (NDC 59676-030-56).
    • Bottle of 84-tablets with child resistant closure (NDC 59676-030-84).
    • 4 mg tablets: Orange, round biconvex, film-coated, debossed with “4” on one side and “EF” on the other side.
    • Bottle of 28-tablets with child resistant closure (NDC 59676-040-28).
    • Bottle of 56-tablets with child resistant closure (NDC 59676-040-56).
    • 5 mg tablets: Brown, round biconvex, film-coated, debossed with “5” on one side and “EF” on the other side.
    • Bottle of 28-tablets with child resistant closure (NDC 59676-050-28).
    Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

    BALVERSATM(erdafitinib) tablets

    1. PATIENTCOUNSELING INFORMATION
    Advise the patient to read the FDA-approved patient labeling (Patient Information).

    FGFR genetic alterations: Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated [seeDosageandAdministration(2.1)].

    Ocular disorders: Advise patients to contact their healthcare provider if they experience any visual changes [see WarningsandPrecautions (5.1)]. In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes, hydrating or lubricating eye gels or ointments frequently, at least every 2 hours during waking hours [seeDosageandAdministration(2.3)].

    Skin, mucous or nail disorders: Advise patients to contact their healthcare provider if they experience progressive or intolerable skin, mucous or nail disorders [see Adverse Reactions(6.1)].

    Hyperphosphatemia: Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed [seeWarningsandPrecautions (5.2)]. During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels. Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with BALVERSA [see Drug Interactions(7.1)].

    Drug Interactions: Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products [seeDrugInteractions(7.1,7.2)].

    Dosing Instructions: Instruct patients to swallow the tablets whole once daily with or without food. If vomiting occurs any time after taking BALVERSA, advise patients to take the next dose the next day. [seeDosageandAdministration(2.1)].

    Missed dose: If a dose is missed, advise patients to take the missed as soon as possible. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose [seeDosageand Administration(2.3)].

    Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy [seeWarningandPrecautions(5.3) andUse inSpecificPopulation(8.1)].

    Advise female patients of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA [seeUseinSpecificPopulations(8.3)].

    Lactation: Advise females not to breastfeed during treatment with BALVERSA and for one month after the last dose [seeUseinSpecificPopulations(8.2)].

    Product of Switzerland

    Manufactured for: Janssen Products, LP Horsham, PA 19044

    Under license from Astex Therapeutics Limited.

    ©2019 Janssen Pharmaceutical Companies

    PATIENT INFORMATION

    BALVERSA™ (bal-VER-sah) (erdafitinib) tablets

    What is BALVERSA?

    BALVERSA is a prescription medicine used to treat adults with bladder cancer (urothelial cancer) that has spread or cannot be removed by surgery:

    • which has a certain type of abnormal “FGFR” gene, and
    • who have tried at least one other chemotherapy medicine that contains platinum, and it did not work or is no longer working. Your healthcare provider will test your cancer for certain types of abnormal FGFR genes and make sure that BALVERSA is right for you.
    It is not known if BALVERSA is safe and effective in children.

    Before taking BALVERSA tell your healthcare provider about all of your medical conditions, including if you:

    • have vision or eye problems.
    • are pregnant or plan to become pregnant. BALVERSA can harm your unborn baby. You should not become pregnant during treatment with BALVERSA.
    Females who can become pregnant:

    ° Your healthcare provider may do a pregnancy test before you start treatment with BALVERSA.

    ° You should use effective birth control during treatment and for 1 month after the last dose of BALVERSA. Talk to your healthcare provider about birth control methods that may be right for you.

    ° Tell your healthcare provider right away if you become pregnant or think you may be pregnant.

    Males with female partners who can become pregnant:

    ° You should use effective birth control when sexually active during treatment with BALVERSA and for 1 month after the last dose.

    • are breastfeeding or plan to breastfeed. Do not breastfeed during treatment and for 1 month after the last dose of BALVERSA.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    How should I take BALVERSA?

    • Take BALVERSA exactly as your healthcare provider tells you.
    • Take BALVERSA 1 time each day.
    • Swallow BALVERSA tablets whole with or without food.
    • Your healthcare provider may change your dose of BALVERSA, temporarily stop or completely stop treatment if you get certain side effects.
    • If you miss a dose of BALVERSA, take the missed dose as soon as possible on the same day. Take your regular dose of BALVERSA the next day. Do not take more BALVERSA than prescribed to make up for the missed dose.
    • If you vomit after taking BALVERSA, do not take another BALVERSA tablet. Take your regular dose of BALVERSA the next day.
    BALVERSATM(erdafitinib) tablets

    What are the possible side effects of BALVERSA? BALVERSA may cause serious side effects, including:

    • Eye problems. Eye problems are common with BALVERSA but can also be serious. Eye problems include dry or inflamed eyes, inflamed cornea (front part of the eye) and disorders of the retina, an internal part of the eye. Tell your healthcare provider right away if you develop blurred vision, loss of vision or other visual changes. You should use artificial tear substitutes, hydrating or lubricating eye gels or ointments at least every 2 hours during waking hours to help prevent dry eyes. During treatment with BALVERSA, your healthcare provider will send you to see an eye specialist.
    • High phosphate levels in the blood (hyperphosphatemia). Hyperphosphatemia is common with BALVERSA but can also be serious. Your healthcare provider will check your blood phosphate level between 14 and 21 days after starting treatment with BALVERSA, and then monthly, and may change your dose if needed.
    The most common side effects of BALVERSA include:

    • mouth sores • low red blood cells (anemia)
    • feeling tired • dry skin
    • change in kidney function •  dry eyes
    • diarrhea •   hair loss
    • dry mouth • redness, swelling, peeling or tenderness, mainly on the
    • nails separate from the bed or poor formation of the nail hands or feet (‘hand-foot syndrome’)
    • change in liver function • constipation
    • low salt (sodium) levels • stomach (abdominal) pain
    • decreased appetite • nausea
    • change in sense of taste • muscle pain
    Tell your healthcare provider right away if you develop any nail or skin problems including nails separating from the nail bed, nail pain, nail bleeding, breaking of the nails, color or texture changes in your nails, infected skin around the nail, an itchy skin rash, dry skin, or cracks in the skin.

    BALVERSA may affect fertility in females who are able to become pregnant. Talk to your healthcare provider if this is a concern for you. These are not all possible side effects of BALVERSA. For more information, ask your healthcare provider or pharmacist.

    Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store BALVERSA?

    • Store BALVERSA tablets at room temperature between 68°F to 77°F (20°C to 25°C).
    Keep BALVERSA and all medicines out of the reach of children.

    General information about the safe and effective use of BALVERSA.

    Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use BALVERSA for a condition for which it was not prescribed. Do not give BALVERSA to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about BALVERSA that is written for healthcare professionals.

    What are the ingredients in BALVERSA? Active ingredient: erdafitinib

    Inactive ingredients:

    Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol, Meglumine, and Microcrystalline Cellulose. Film Coating (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcohol-partially hydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red (for the orange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only).

    Manufactured by:Janssen-Cilag SpA, Latina, Italy

    Manufactured for:Janssen Products, LP, Horsham, PA 19044

    © 2019 Janssen Pharmaceutical Companies

    For more information call Janssen Products, LP at 1-800-526-7736 (1-800-JANSSEN) or go to www.BALVERSA.com.

    This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: April 2019

    Published Date: April 16th, 2019

    Published April 16, 2019
  • ESMO 2019: EV-103: Initial Results of Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

    Barcelona, Spain (UroToday.com) Platinum-based chemotherapy remains the standard of care for patients with locally advanced or metastatic urothelial carcinoma. Despite the use of first-line PD-1/PD-1L inhibitors, 71–76% of patients who are cisplatin-ineligible do not respond to treatment. Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in metastatic urothelial carcinoma. Enfortumab vedotin monotherapy data are encouraging, initially presented at ASCO 2019, demonstrating a 44% response rate (12% complete response). Perhaps combination therapy may provide additional benefit – the working hypothesis is that combination enfortumab vedotin plus pembrolizumab is feasible, safe, and may lead to improved responses compared to historical controls in the first-line cisplatin-ineligible setting. At the 2019 European Society for Medical Oncology annual meeting (ESMO) proffered paper session, Dr. Hoimes and colleagues presented initial data on a cohort of cisplatin-ineligible patients receiving first line enfortumab vedotin + pembrolizumab.

    Published September 28, 2019
  • ESMO 2019: IMvigor130: Efficacy and Safety of Atezolizumab as Monotherapy or Combined with Platinum-based Chemotherapy vs Placebo + Platinum-based Chemotherapy in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma

    Barcelona, Spain (UroToday.com) First-line metastatic urothelial carcinoma treatment includes cisplatin or carboplatin-based chemotherapy or checkpoint inhibitors, depending on patient eligibility and PD-L1 status. Approximately 50% of patients are platinum ineligible and they may receive inferior carboplatin-based regimens. In July 2018, the FDA and EMA revised the first-line label for atezolizumab and pembrolizumab based on IMDC assessments. IMvigor130 is a phase 3, global, multicenter, randomized, partially blinded study evaluating atezolizumab (anti–PD-L1) alone or with platinum-based chemotherapy vs placebo + platinum-based chemotherapy in untreated metastatic urothelial carcinoma. At the ESMO 2019 Presidential session, Dr. Enrique Grande presented the final PFS and interim overall survival (OS) results for IMvigor130.

    Published October 1, 2019
  • ESMO 2019: Invited Discussant: IMvigor130: Phase III Study of Atezolizumab with or without Platinum-Based Chemotherapy in Previously Untreated Metastatic Urothelial Carcinoma

    Barcelona, Spain (UroToday.com) Atezolizumab has received regulatory approval for patients with locally advanced or metastatic urothelial carcinoma.  This has occurred for both cisplatin-ineligible patients in the first-line setting and also for those in the post-platinum treated setting.1, 2  In other malignancies, such as lung cancer, major advances have been made in treatment outcomes when cytotoxic chemotherapy has been combined with up front checkpoint inhibition with immune-oncology (IO) agents.  Hence, multiple efforts have been launched with combination chemotherapy and atezolizumab, an anti-PD-L1 antibody as well as pembrolizumab, an anti-PD-1 antibody, in the first-line metastatic urothelial carcinoma setting.

    Published October 2, 2019
  • ESMO 2019: Phase 2 TROPHY-U-01 Open-Label Study of Patients Receiving Sacituzumab Govitecan with Metastatic Urothelial Cancer After Failure of Platinum-Based Regimens or Immunotherapy

    Barcelona, Spain (UroToday.com) Platinum-based chemotherapy has been the standard first-line therapy for patients with metastatic urothelial cancer (mUC). Historically, response to standard of care second-line chemotherapy regimens is < 15%. Although immune checkpoint inhibitors (ICIs) now provide another option for patients with platinum-refractory mUC, response rates are similarly low, highlighting a critical need for novel therapeutic agents in this disease setting. Dr. Scott Tagawa presents the initial results from TROPHY-U-01: A Phase 2 open-label study of Sacituzumab Govitecan (SG) in patients with mUC after progression on platinum-based chemotherapy or an ICI.

    Published September 28, 2019

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