Advanced Bladder Cancer COE Articles

Articles

  • 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
  • Efficacy of Maintenance Avelumab After Chemotherapy in Advanced Urothelial Carcinoma - Expert Commentary

    The standard of care first-line treatment for advanced urothelial carcinoma (aUC) is platinum-based chemotherapy, followed by avelumab (anti-PD-L1), for maintenance treatment in patients without progression. The JAVELIN trial confirmed that maintenance avelumab was associated with significantly prolonged overall survival (OS) and progression-free survival (PFS). Bakaloudi et al. set out to characterize clinical outcomes of switch maintenance avelumab in a real-world cohort of patients with aUC.
    Published September 5, 2023
  • 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
  • Enfortumab Vedotin Versus Chemotherapy for Advanced Urothelial Carcinoma - Expert Commentary

    Patients with advanced urothelial carcinoma (UC) still have low 5-year survival rates. Most patients experience disease progression after treatment with chemotherapy or PD-1 inhibitors. Enfortumab vedotin (EV) is an antibody-drug conjugate that targets Nectin-4, a protein highly expressed in UC. A recent study by Rosenberg et al. reports long-term outcomes from EV-301, an open-label phase III trial for EV versus chemotherapy in previously treated patients with advanced UC.
    Published October 26, 2023
  • 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
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    Published October 2, 2019
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    Published September 28, 2019
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    Published September 16, 2021
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    Published September 10, 2022
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    Published October 22, 2023
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    Published October 22, 2023
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    Published October 21, 2023
  • ESMO Virtual Congress 2020: EV-302: Enfortumab Vedotin plus Pembrolizumab and/or Chemotherapy, vs Chemotherapy Alone, in Untreated Locally Advanced or Metastatic Urothelial Cancer

    (UroToday.com) Platinum-based chemotherapy is the mainstay of first-line treatment for medically eligible patients with advanced urothelial carcinoma (UC). Unfortunately, up to 50% of patients are unable to receive cisplatin, and disease progression often develops even for patients who receive cisplatin. Immunotherapy with checkpoint blockade is a standard of care option for platinum-ineligible patients or those who have progressed on platinum therapy. Antibody-drug conjugates that are targeted to a highly expressed tumor protein and conjugated to a chemotherapy payload, such as enfortumab vedotin, are emerging as effective therapies for subsequent lines of treatment. 
    Published September 23, 2020
  • ESMO Virtual Congress 2020: Patient-Reported Outcomes from JAVELIN Bladder 100: Avelumab First-Line Maintenance Plus Best Supportive Care vs Best Supportive Care Alone For Advanced Urothelial Carcinoma

    (UroToday.com) Urothelial carcinoma has a substantial impact on patient qualify of life. Patients may experience a multitude of disease-related symptoms, including pain, urinary frequency, physical changes, and mental health issues, with all affect quality of life. Additionally, treatment side effects of chemotherapy have been shown to reduce the quality of life in patients with advanced urothelial carcinoma. In the phase III JAVELIN Bladder 100 trial, avelumab (anti–PD-L1) first-line maintenance plus best supportive care significantly prolonged overall survival (primary endpoint) versus best supportive care alone in patients with advanced urothelial carcinoma without disease progression with first-line induction chemotherapy (HR 0.69, 95% CI 0.56-0.86).1 At the European Society of Medical Oncology (ESMO) 2020 Virtual Congress, Dr. Thomas Powles and colleagues reported patient-reported outcomes from the JAVELIN Bladder 100 study.

    Published September 18, 2020
  • ESMO Virtual Congress 2020: Subgroup Analyses from JAVELIN Bladder 100: Avelumab first-line (1L) maintenance + Best Supportive Care (BSC) vs BSC Alone with 1L Chemotherapy for Advanced Urothelial Carcinoma

    (UroToday.com) Advanced urothelial carcinoma has among the worst prognosis for tumors treated by genitourinary oncologists. Standard of care dictates that patients receive platinum-based induction chemotherapy. However, even with this treatment, rates of recurrence and disease progression are high and overall survival is quite short due to the development of chemotherapy resistance. In the JAVELIN Bladder 100 study which was reported at ASCO 2020 Virtual Annual Meeting, the addition of avelumab, a PD-L1 directed therapy, as first-line maintenance to best supportive care demonstrated improvements in overall survival for patients who did not have disease progression during their initial cytotoxic chemotherapy induction.
    Published September 18, 2020
  • ESMO Virtual Congress 2020: TROPHY-U-01 Cohort 1 Final Results: A Phase 2 Study of Sacituzumab Govitecan (SG) in Metastatic Urothelial Cancer That Has Progressed After Platinum and Checkpoint Inhibitors

    (UroToday.com) Treatment options for advanced urothelial cancer that has progressed through platinum chemotherapy and immune checkpoint blockade consist of (1) single agent chemotherapy, (2) FGFR inhibitor therapyfor tumors harboring susceptible alterations, and (3) the antibody-drug conjugate enfortumab vedotin.

    Sacituzumab govitecan is an antibody-drug conjugate containing an antibody against the epithelial cell surface molecule Trop-2 that is attached to a chemotherapy payload of SN-38 (a potent derivative of irinotecan). This drug does not require internalization into tumor cells to deliver its payload, and is notable for a high drug-to-antibody ratio amongst antibody-drug conjugates. Clinical data from the urothelial carcinoma cohort of IMMU-132-01 revealed a 31% overall response rate (ORR) with this agent. In this presentation, Yohann Loriot, MD, MSc presented data from cohort 1 of the TROPHY-U-01 study involving the treatment of 113 patients with metastatic urothelial carcinoma that progressed on prior platinum and immune checkpoint therapy. Interim analysis from this cohort was previously presented at the European Society of Medical Oncology (ESMO) 2019 meeting, suggesting an ORR rate of 29% in the 35 patients analyzed at that point.

    The study design is shown below. The drug is administered at a dose of 10 mg/kg on days 1 and 8 or a 21-day cycle. The primary objective of this study was the objective response rate, with a null hypothesis of ORR <= 12%.

    TROPHY-U-O1_StudyDesign.png

    As of the data cut-off of May 18, 2020, 16 of the 113 patients evaluated were continuing on treatment. Two-thirds of patients had discontinued therapy due to progressive disease, and three patients discontinued therapy because they passed away. The median age of the cohort was 66, and the median number of prior anticancer therapies was 3.

    Demographic_Baseline_Characteristics.png

    The trial met its primary endpoint with an objective response rate of 27% (31 patients). There were 6 complete responses. The median duration of response was 5.9 months, and the median time to onset of response was 1.6 months. 76% of patients showed reductions in tumor size on treatment. The clinical course of the 31 responders are shown below.

    Response_LBA24.png

    The median progression-free survival in this cohort was 5.4 months, and the median overall survival was 10.5 months.

    The most common treatment-related adverse event was diarrhea, with 9% of patients have a grade 3 event, consistent with what might be expected from an irinotecan-derived drug. Neutropenia occurred in 46% of patients.

    TreatmentRelatedAEs_LBA24.png

    These results confirm the clinical activity of sacituzumab govitecan in heavily pre-treated metastatic urothelial carcinoma patients who progressed on platinum and immune checkpoint blockade therapy. The ORR of 27% compares favorably to single-agent chemotherapy in this pre-treated setting (10%, PFS 2-3 months). Importantly, in the Q&A setting, Dr. Loriot reported that 10 patients in this cohort was previously treated with enfortumab vedotin. Of these 10 patients, 3 had a partial response including 2 patients whose disease had progressed on enfortumab.

    The phase 3 confirmatory trial of sacituzumab in urothelial carcinoma is underway (TROPiCS-04, NCT04527991). The schema for that trial is shown below. 

    TROPiCS-04_LBA24.png

    Presented by: Yohann Loriot, MD, MSc, Department of Cancer Medicine, INSERM U981, Villejuif, France

    Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.
    Published September 19, 2020
  • Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy in Patients with Locally Advanced Bladder Cancer - Expert Commentary

    Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) neoadjuvant chemotherapy is a standard of care for muscle-invasive urothelial bladder cancer. However, gemcitabine-cisplatin (GC) is equally effective and associated with less toxicity in the metastatic setting. This has been extrapolated to the neoadjuvant setting in clinical practice. A recent study by Niedersüss-Beke et al. in the journal Oncologyprospectively evaluated the clinical outcomes of neoadjuvant GC in patients with locally advanced urothelial cancer.
    Published April 28, 2017
  • Gemcitabine-Eribulin in Cisplatin-Ineligible Patients with Metastatic Urothelial Carcinoma - Expert Commentary

    The optimal treatment for cisplatin-ineligible patients with metastatic urothelial cancer is unknown. A recent study published by Sadeghi et al. in the Journal of Clinical Oncology1 examined the efficacy of the gemcitabine-eribulin combination in this patient population.

    Cisplatin-ineligibility was defined as a creatinine clearance <60 ml/min and ≥30ml/min, grade 2 or above hearing loss and grade 2 or higher neuropathy. The study enrolled twenty-four patients between 2015 and 2017. Subjects received 1,000 mg/m2 of gemcitabine intravenously 30 minutes before 1.4 mg/m2 eribulin on day 1 and 8 in 21-day cycles until progression or unacceptable toxicity. The median age of enrolled patients was 73 years (range 62-88 years). Most patients had a performance status of 0 or 1. The majority of patients (16/24) had lymph node metastases, and several patients had visceral metastases.

    The observed objective response rate was 50% (95% CI, 29% to 71%) in 12/24 patients. The median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). Common toxicities included fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), constipation, nausea, and thrombocytopenia (42% each).

    This study demonstrated the efficacy of the combination of gemcitabine-eribulin in cisplatin-ineligible metastatic urothelial cancer patients. Prospective trials comparing the efficacy of carboplatin-based regimens, immunotherapy, and gemcitabine-eribulin combinations are needed to determine the optimal treatment regimen.

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

    Reference: 
    1. Sadeghi, Sarmad, Susan G. Groshen, Denice D. Tsao-Wei, Rahul Parikh, Amir Mortazavi, Tanya B. Dorff, Cheryl Kefauver et al. "Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653)." Journal of Clinical Oncology (2019): JCO-19.

    Read the Abstract
    Published September 9, 2019
  • IBCN 2019: Genomic Classifier to Predict Luminal Bladder Tumors

    Aarhus, Denmark (UroToday.com) Joep J. de Jong from the Erasmus MC Cancer Institute in Rotterdam discussed efforts at developing a genomic classifier to predict clinically aggressive luminal bladder tumors. 

    Published October 7, 2019
  • IBCN 2022: Genome-Wide Circulating Tumor DNA for Monitoring Treatment Response and Metastatic Relapse in Bladder Cancer

    (UroToday.com) Approximately 45% of patients with localized muscle-invasive bladder cancer treated with neoadjuvant chemotherapy followed by radical cystectomy will develop recurrence, thus making biomarkers for early detection of minimal residual disease a critical unmet need. Tumor informed detection of mutations in cell-free DNA (cfDNA) has shown promising results in that respect. In this study presented by Dr. Nordentoft, a whole-genome sequencing (WGS) approach to circulating tumor DNA (ctDNA) was applied for sensitive monitoring of Minimal Residual Disease (MRD).

    Published October 2, 2022
  • Immuno-Oncology for Bladder Cancer

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 2
    Published Date: June 2018

    Initial Considerations

    From BCG to interferon gene therapy, physicians have treated bladder cancer with immunotherapy for decades. Treatment particulars generally depend on whether bladder cancer is non-muscle invasive, muscle-invasive, or metastatic. About 75% of patients have non-muscle invasive bladder cancer (NMIBC),1 which is considered high-risk if it consists of non-invasive papillary carcinoma (TaHG),ins
    Published September 26, 2018
  • Immuno-Oncology: The Urologist's Role

    Published in Everyday Urology - Oncology Insights: Volume 4 Issue 1
    Published Date: March 2019

    This is an extraordinary time in urology. After decades of relative stagnation, patients with urothelial carcinoma are receiving approved immuno-oncologic drugs that significantly extend survival and are safer and more tolerable than chemotherapy.  The success of these treatments in metastatic bladder cancer has generated strong interest and promising early results for their use in localized disease.
    Published June 18, 2019
  • Long-Term Results from the S1314 Study of Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer - Expert Commentary


    The standard of care for muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. Studies have documented the clinical benefit of dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) or gemcitabine plus cisplatin (GC). The COXEN approach was developed to use gene expression data as a potential biomarker that predicts patients who are likely to benefit more from GC versus ddMVAC., Flaig et al. recently reported the long-term results of the S1314 trial.
    Published September 8, 2023
  • Neoadjuvant Chemotherapy Prior to Radical Cystectomy for Muscle-Invasive Bladder Cancer with Variant Histology - Expert Commentary

    Neoadjuvant chemotherapy is a standard of care for patients with urothelial muscle-invasive bladder cancer. Histologic variants of bladder cancer are less common but often clinically aggressive. Understanding whether neoadjuvant chemotherapy results in the same benefit in histological variants as in urothelial bladder cancer is crucial.
    Published August 8, 2017
  • Nivolumab in Patients with Advanced Platinum-Resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-Up from CheckMate 275 - Expert Commentary

    Nivolumab is an FDA-approved immune checkpoint for treating platinum-resistant metastatic or surgically unresectable urothelial carcinoma (mUC). The development of predictive biomarkers to predict response to immune checkpoint inhibitors have been challenging. 
    Published July 2, 2020
  • Response to Platinum Reintroduction After Immune Checkpoint Inhibitors for Metastatic Urothelial Carcinoma - Expert Commentary

    Immune checkpoints inhibitors (ICIs) are approved as a second line of treatment for metastatic urothelial carcinoma (mUC) patients with progression on cisplatin-based chemotherapy. Chemotherapy is rarely reintroduced in these patients after the ICI.
    Published March 8, 2019
  • SES AUA 2021: Avelumab First-Line Maintenance + Best Supportive Care (BSC) vs BSC Alone with 1L Chemotherapy for Advanced Urothelial Carcinoma: JAVELIN Bladder 100 Subgroup Analyses

    (UroToday.com) Advanced urothelial carcinoma carries among the worst prognoses for tumors treated by genitourinary oncologists. Standard of care dictates that patients receive platinum-based induction chemotherapy. However, even with this treatment, rates of recurrence and disease progression are high and overall survival is quite short due to the development of chemotherapy resistance. In the JAVELIN Bladder 100 study which was reported at ASCO 2020 Virtual Annual Meeting and subsequently published in the New England Journal of Medicine, the addition of avelumab, a PD-L1 directed therapy, maintenance to best supportive care following induction chemotherapy demonstrated improvements in overall survival for patients who did no have disease progression during their initial cytotoxic chemotherapy induction.
    Published April 23, 2021
  • SES AUA 2021: Modern Bladder Cancer Warfare: Does "Leave No Bladder Behind" Ethos Still Apply?

    (UroToday.com) The State of the Art lecture at the 2021 virtual annual meeting of the Southeastern Section of the AUA was provided by Dr. Alex Kutikov who discussed the current applications for radical cystectomy and perhaps to spare certain bladders while minimizing risk of disease progression. 
    Published April 25, 2021
  • SIU 2019: Debate - Chemotherapy is Better than Immunotherapy as Neoadjuvant Therapy for Muscle Invasive Bladder Cancer

    Athens, Greece (UroToday.com) Dr. Roland Seiler presented after Dr. Andrea Necchi, supporting the role of chemotherapy in the neoadjuvant setting of treating muscle invasive bladder cancer (MIBC), as opposed to immunotherapy.

    Published October 20, 2019
  • SIU 2019: pT0 after Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Carcinoma of the Bladder: Implications for Bladder Preservation

    Athens, Greece (Urotoday.com) Neoadjuvant chemotherapy (NAC) in bladder cancer has been proven to improve overall survival in patients with muscle-invasive bladder cancer (MIBC) over 15 years ago1. Accurate preoperative prediction of pathological T0 could perhaps spare cystectomy in a significant portion of patients2. NAC compared to TURBT alone has shown a significant advantage with a higher percentage of patients reaching pT0 (30% vs. 12%). Patients reaching Pt0 following NAC have significantly better survival curves than those not reaching Pt0, perhaps enabling them to keep their bladder and not undergo radical cystectomy.

    Published October 19, 2019
  • SUO - AUA 2020 Summer Webcast: Identical, Fraternal or Disparate Twins? The Case of Bladder Urothelial Carcinoma and Upper Tract Urothelial Carcinoma

    (UroToday.com) At the Society of Urologic Oncology (SUO) Summer Virtual Webcast, Bishoy Faltas, MD, from Weill Cornell compared the genetic components of the bladder and upper tract urothelial carcinoma. Upper tract urothelial carcinoma comprises 5-10% of all urothelial carcinomas with a unique epidemiologic association with Arsenic exposure and aristolochic acid. Upper tract urothelial carcinoma presents with muscle invasion (pT2+) in 60% of cases, as compared to 20-30% of cases for bladder urothelial cancer. Upper tract urothelial carcinoma has more advanced disease at presentation but has similar outcomes to patients with bladder cancer after controlling for disease stage. It has been postulated that patients with upper tract urothelial carcinoma have more rapid invasion of the muscularis propria secondary to a thinner wall.

    Published July 19, 2020
  • SUO 2019: Immunotherapy in Bladder Cancer: Targets and Surgical Timing

    Washington, DC (UroToday.com) As part of the Research Scholars Update at the 20th Annual Meeting of the Society of Urologic Oncology, Dr. Karen Wheeler presented her work on immunotherapy and bladder cancer. Previous work has shown that surgery can induce an immune suppressive state. Using a mouse model, Dr. Wheeler assessed survival of mice with intravenous MB49 (lung metastasis) or intravesical MB49 (orthotopic) demonstrating that surgery can worsen survival in the metastatic model but not in an orthotopic (bladder cancer) model:

    Published December 6, 2019
  • SUO 2019: Organ Preservation in Urologic Cancers - Muscle-Invasive Bladder Cancer

    Washington, DC (UroToday.com) Organ preservation in bladder cancer has been a widely debated topic with polarizing views from different centers and researchers worldwide. At the SUO 2019 meeting in Washington, DC, during the session on organ preservation in urologic cancers, Professor Robert Huddart from the Royal Marsden presented on Muscle-invasive bladder cancer (MIBC). 
    Published December 5, 2019
  • SUO 2020: Navigating Novelty in Advanced Disease: Current Evidence and Adaptive Strategies for Sequencing Immune Checkpoint Inhibitors, FGFR Inhibitors, and Antibody-Drug Conjugates

    (UroToday.com) At the 2020 Society of Urologic Oncology (SUO) Annual Virtual Meeting, Dr. Neal Shore chaired a session examining the use of newer and emerging agents in bladder cancer, which highlighted a presentation by medical oncologist Dr. Robert Dreicer discussing novel treatment options for patients with advanced bladder cancer. Dr. Dreicer notes that in 1993 cisplatin chemotherapy was approved for the treatment of advanced disease, followed by a long drought for other systematic therapy options until the last few years. Currently, the standards of care for initial therapy in advanced urothelial cancer are summarized in the following table:

    standards of care for initial therapy in advanced urothelial cancer


    Patients that are unfit for cisplatin-based chemotherapy represent 40-60% of patients with advanced urothelial cancer, however, there are widely accepted definitions for who is truly unfit, including (i) ECOG of 2 or greater, (ii) creatinine clearance ≤ 60 ml/min, (iii) grade 2 or greater peripheral neuropathy/hearing loss, (iv) NYHA class III heart failure. Taking into consideration all lines of therapy for standard of care for advanced urothelial carcinoma, the current landscape is as follows:

    lines of therapy for standard of care for advanced urothelial carcinoma

    The KEYNOTE-052 trial was a multicenter, single-arm, Phase II study that assessed pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic disease.1 Dr. Dreicer highlights that 11% of these patients were ≥ 85 years of age, 42% had ECOG performance status 2, and 85% had visceral disease. Among 370 patients, the objective response rate was 29% (95% confidence interval [CI] 25-34%), including 7% (95% CI 25-34%) of patients with complete response, and 22% (95% CI 18-27%) with partial response.

    First presented at the 2019 European Society of Medical Oncology (ESMO 2019) Annual Meeting, the IMvigor130 trial is a Phase III trial assessing atezolizumab as monotherapy or combined with platinum-based chemotherapy vs placebo + platinum-based chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. This trial enrolled 1,213 platinum-based chemotherapy-eligible patients with metastatic urothelial carcinoma. Patients were randomized 1:1:1 to Arm A (atezolizumab + platinum-based chemotherapy [gemcitabine + either cisplatin or carboplatin]), Arm B (atezolizumab) or Arm C (placebo + platinum-based chemotherapy). The co-primary efficacy endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS) (Arm A vs C) and OS (Arm B vs C) per RECIST 1.1. The IMvigor130 trial design is as follows:

    IMvigor130 trial efficacy points

    With a median follow-up of 11.8  months, the median PFS was 8.2  months in Arm A vs 6.3  months in Arm C (hazard ratio [HR] 0.82, 95% CI 0.70-0.96; p = 0.007). The PFS benefit of combination therapy was also robust across most subgroups. The comparison of OS did not cross the prespecified interim efficacy boundary, with a median of 16.0  months in Arm A and 13.4  months in Arm C (HR 0.83, 95% CI 0.69-1.00; p = 0.027). For Arm B vs C, the median OS was 15.7 months and 13.1  months, respectively (HR 1.02, 95% CI 0.83-1.24), for ITT patients and not estimable and 17.8  months, respectively (HR 0.68, 95% CI 0.43-1.08), for PD-L1 IC2/3 patients.

    The KEYNOTE-361 trial was recently presented at the ESMO 2020 virtual meeting, a Phase III trial randomizing patients with advanced or metastatic disease 1:1:1 to pembrolizumab + gemcitabine + cisplatin or carboplatin versus pembrolizumab versus gemcitabine + cisplatin or carboplatin. The dual primary endpoints for this trial were PFS per RECIST v1.1 by blinded review and overall survival. Overall survival in the intention to treat population was 17.0 months (95% CI 14.5-19.5) in the pembrolizumab plus chemotherapy arm versus 14.3 months (95% CI 12.3-16.7) in the chemotherapy arm (HR 0.86, 95% CI 0.72-1.02, p=0.0407).

    In arguably one of the most influential trials in the last year, the Phase III JAVELIN Bladder 100 trial showed that avelumab first-line maintenance plus best supportive care significantly prolonged overall survival (primary endpoint) versus best supportive care alone in patients with advanced urothelial carcinoma without disease progression with first-line induction chemotherapy (HR 0.69, 95% CI 0.56-0.86):2

    OS in JAVELIN Bladder 100 trial

    Furthermore, in the PD-L1+ population median OS was not reached for avelumab plus best supportive care (95% CI 20.3 to not reached) versus 17.1 months (95% CI 13.5-23.7) for best supportive care alone (HR 0.56, 95% CI 0.40-0.79).

    Shifting gears, Dr. Dreicer also discussed erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor that is approved in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma and susceptible FGFR3/2 alterations following ≥ 1 line of platinum-based chemotherapy. Approval of erdafitinib was based on data from the primary analysis of the pivotal BLC2001 trial in adult patients with previously treated locally advanced or metastatic urothelial carcinoma and FGFR3/2 alterations.3 At the final analysis of the BLC2001 study, among all patients treated with the optimal schedule of erdafitinib, the objective response rate was 40%, median duration of response was 5.98 months, median progression-free survival was 5.5 months, and median overall survival was 11.3 months.

    Enfortumab vedotin is an antibody-drug conjugate that is comprised of a fully human monoclonal antibody conjugated to the clinically validated microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. Enfortumab vedotin targets Nectin-4, a transmembrane protein. In EV-101, a Phase I dose-escalation/expansion study n=155), enfortumab vedotin had a confirmed objective response rate of 43%, and duration of response of 7.4 months; median overall survival was 12.3 months, and the overall survival rate at 1 year was 51.8%.3 EV-301 is a global Phase III study of enfortumab vedotin versus physician choice of docetaxel/paclitaxel/vinflunine in patients previously treated with platinum and checkpoint inhibitors. In a press release on September 18, 2020, this trial was stopped early by the DMC as enfortumab vedotin significantly improved overall survival, with a 30% reduction in death (HR 0.70, 95% CI 0.56-0.89, p=0.001).

    Dr. Dreicer concluded with several sequencing questions/comments in advanced urothelial cancer therapeutics:

    • There is a relative wealth of therapeutic options, which creates challenges
    • There is no data to support checkpoint inhibitor/chemotherapy combinations upfront
    • The switch maintenance data is compelling
    • There is data to support adjuvant therapy for high-risk patients with checkpoint inhibitor therapy
    • Next-generation sequencing needs to become part of the management paradigm
    • Single-agent “salvage” chemotherapy’s time is gone
    • Novel non-chemotherapy combinations for upfront therapy are being evaluated in Phase III trials

    Presented by: Robert Dreicer, MD, Section Head, Medical Oncology, Deputy Director, University of Virginia Cancer Center, University of Virginia, Charlottesville, Virginia

    Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC

    References:

    1. Balar, Arjun V., Daniel Castellano, Peter H. O'Donnell, Petros Grivas, Jacqueline Vuky, Thomas Powles, Elizabeth R. Plimack 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." The Lancet Oncology 18, no. 11 (2017): 1483-1492.

    2. Powles, Thomas, Se Hoon Park, Eric Voog, Claudia Caserta, Begoña P. Valderrama, Howard Gurney, Haralabos Kalofonos et al. "Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma." New England Journal of Medicine 383, no. 13 (2020): 1218-1230.

    3. Loriot, Yohann, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert Huddart, Earle Burgess, Mark Fleming et al. "Erdafitinib in locally advanced or metastatic urothelial carcinoma." New England Journal of Medicine 381, no. 4 (2019): 338-348.

    4. Rosenberg, Jonathan, Srikala S. Sridhar, Jingsong Zhang, David Smith, Dean Ruether, Thomas W. Flaig, Joaquina Baranda et al. "EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4–Positive Solid Tumors, Including Metastatic Urothelial Carcinoma." Journal of Clinical Oncology 38, no. 10 (2020): 1041.
    Published December 4, 2020
  • Survival Outcomes and Parameters of Switch Maintenance - Expert Commentary

    Platinum-based chemotherapy is the standard of care for first-line treatment in patients with advanced urothelial carcinoma. Switch maintenance therapy with a drug with a different mode of action and better tolerability can enhance the clinical benefit of first-line chemotherapy.
    Published November 14, 2023
  • The Advanced Bladder Clinic: Are You Ready?

    Published in Everyday Urology - Oncology Insights: Volume 5, Issue 1
    Published Date: March 2020

    In 2015, cisplatin-ineligible patients with metastatic urothelial carcinoma could not be offered a first-line treatment option capable of prolonging their survival. Also, a paucity of second-line treatments resulted in these same patients usually surviving for only 3 to 6 months after progressing on platinum-treatment.
    Published April 16, 2020
  • The Current Landscape of Neoadjuvant Chemotherapy in Cisplatin Eligible Patients with Clinically Localized, Muscle Invasive Bladder Cancer

    Introduction

    Bladder cancer is currently the 10th most commonly diagnosed malignancy worldwide, with an estimated 110,500 men and 70,000 women diagnosed annually.1 While the majority of patients are diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are initially diagnosed with muscle invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.1

    Written by: Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
    References:
    1. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol 2013;63(2):234-41.
    2. Flaig TW, Speiss PE, Abern M, et al. NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022. J Natl Compr Canc Netw 2022;20(8):866-878.
    3. EAU Guidelines: Muscle-invasive and Metastatic Bladder Cancer. Accessed: December 27, 2022.
    4. ASCO Cancer.Net: Bladder Cancer – Statistics. Accessed: December 27, 2022.
    5. Martinez-Pineiro JA, Martin MG, Arovena F, et al. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995;153(3 Pt 2):964-73.
    6. Rintala E, Hannisdahl E, Fossa SD, et al. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol 1993;27(3):355-62.
    7. Malmstrom PU, Rintala E, Wahlqvist R, et al. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996;155(6):1903-6.
    8. Sherif A, Rintala E, Mestad O, et al. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer -- Nordic cystectomy trial 2. Scand J Urol Nephrol 2022;36(6):419-25.
    9. International collaboration of trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party, et al. Neoadjuvant cisplatin,methotrexate,and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 1999;354(9178):533-40.
    10. International Collaboration of Trialists, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011;29(16):2171-7.
    11. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-66.
    12. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361(9373):1927-34.
    13. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-5.
    14. Kitamura H, Tsukamoto T, Shibata T, et al. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol 2014;25(6):1192-8.
    15. Dash A, Pettus JA, Herr H, et al. A Role for Neoadjuvant Gemcitabine Plus Cisplatin in Muscle-Invasive Urothelial Carcinoma of the Bladder: A Retrospective Experience. Cancer 2008;113(9):2471-7.
    16. Goel S, Sinha EJ, Bhaskar V, et al. Role of gemcitabine and cisplatin as neoadjuvant chemotherapy in muscle invasive bladder cancer: Experience over the last decade. Asian J Urol 2019;6(3):222-9.
    17. Iyer G, Tully CM, Zabor EC, et al. Neoadjuvant Gemcitabine-Cisplatin Plus Radical Cystectomy-Pelvic Lymph Node Dissection for Muscle-invasive Bladder Cancer: A 12-year Experience. Clin Genitourin Cancer 2020;18(5):387-94.
    18. Osman MA, Gabr AM, Elkady MS. Neoadjuvant chemotherapy versus cystectomy in management of stages II, and III urinary bladder cancer. Arch Ital Urol Androl 2014;86(4):278-83.
    19. Yafi FA, Aprikian AG, Chin JL, et al. Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience. BJU Int 2011;108(4):539-45.
    20. Pfister C, Gravis G, Flechon A, et al. Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Secondary Endpoints: Chemotherapy Toxicity and Pathological Responses. Eur Urol 2021;29(2):214-21.
    21. Pfister C, Gravis G, Flechon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40(18):2013-22.

     

     

     

    Published March 21, 2023
  • The Current Landscape of Neoadjuvant Chemotherapy/Immunotherapy Combinations in Patients with Clinically Localized, Muscle Invasive Bladder Cancer

    Introduction

    Bladder cancer is currently the 10th most commonly diagnosed malignancy worldwide. It is estimated that approximately 110,500 men and 70,000 women are annually diagnosed with bladder cancer worldwide.1 While the majority of patients are initially diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are diagnosed with muscle invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.1

    Written by: Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
    References:

    References

    1. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol 2013;63(2):234-41.
    2. Flaig TW, Speiss PE, Abern M, et al. NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022. J Natl Compr Canc Netw 2022;20(8):866-878.
    3. EAU Guidelines: Muscle-invasive and Metastatic Bladder Cancer.  Accessed: December 27, 2022.
    4. ASCO Cancer.Net: Bladder Cancer – Statistics. Accessed: December 27, 2022.
    5. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-5.
    6. Pfister C, Gravis G, Flechon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40(18):2013-22.
    7. Rhea LP, Mendez-Marti S, Kim D, Aragon-Chin JB. Role of immunotherapy in bladder cancer. Cancer Treat Res Commun 2021;26:100296.
    8. Rose TL, Harrison MR, Deal AM, et al. Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol 2021;39(28):3140-8.
    9. Funt SA, Lattanzi M, Whiting K, et al. Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial. J Clin Oncol 2022;40(12):1312-22.
    Published March 21, 2023
  • The Current Landscape of Neoadjuvant Immunotherapy Agent Combinations in Patients with Clinically Localized, Muscle Invasive Bladder Cancer

    Introduction

    Bladder cancer is currently the 10th most commonly diagnosed malignancy worldwide. It is estimated that approximately 110,500 men and 70,000 women are annually diagnosed with bladder cancer worldwide.1 While the majority of patients are diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are initially diagnosed with muscle-invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.1

    Written by: Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
    References:
    1. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol 2013;63(2):234-41.
    2. Flaig TW, Speiss PE, Abern M, et al. NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022. J Natl Compr Canc Netw 2022;20(8):866-878.
    3. EAU Guidelines: Muscle-invasive and Metastatic Bladder Cancer. Accessed: December 27, 2022.
    4. ASCO Cancer.Net: Bladder Cancer – Statistics. Accessed: December 27, 2022.
    5. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-5.
    6. Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol 2011;12: 211–4.
    7. Rhea LP, Mendez-Marti S, Kim D, Aragon-Chin JB. Role of immunotherapy in bladder cancer. Cancer Treat Res Commun 2021;26:100296.
    8. Pfister C, Gravis G, Flechon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40(18):2013-22.
    9. Van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med 2020;26(12):1839-44.
    10. Danaher P, Warren S, Lu R, et al. Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA).J Immunother Cancer 2018;6(1):63.a
    11. Gao J, Navai N, Alhalabi O, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med 2020;26(12):1845-51.
    12. Li R, Steinberg GD, Uchio EM, et al. CORE1: Phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with nonmuscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG). J Clin Oncol 2022; 2022 ASCO Annual Meeting I.
    Published March 20, 2023
  • The Current Landscape of Neoadjuvant Single Agent Therapy in Patients with Cisplatin Ineligible Clinically Localized, Muscle Invasive Bladder Cancer

    Introduction

    Bladder cancer is currently the 10th most commonly diagnosed malignancy worldwide. It is estimated that approximately 110,500 men and 70,000 women are annually diagnosed with bladder cancer globally.1 While the majority of patients are diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are initially diagnosed with muscle invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.1

    Written by: Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
    References:
    1. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol 2013;63(2):234-41.
    2. Flaig TW, Speiss PE, Abern M, et al. NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022. J Natl Compr Canc Netw 2022;20(8):866-878.
    3. EAU Guidelines: Muscle-invasive and Metastatic Bladder Cancer. Accessed: December 27, 2022.
    4. ASCO Cancer.Net: Bladder Cancer – Statistics. Accessed: December 27, 2022.
    5. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-5.
    6. Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol 2011;12: 211–4.
    7. Rhea LP, Mendez-Marti S, Kim D, Aragon-Chin JB. Role of immunotherapy in bladder cancer. Cancer Treat Res Commun 2021;26:100296.
    8. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018;36(34):3353-60.
    9. Basile G, Banidin M, Gibb EA, et al. Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial. Clin Cancer Res 2022;28(23):5107-14.
    10. Powles T, Kockx M, Rodriguez-Vida, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 2019; 25(11):1706-14.
    11. Pfister C, Gravis G, Flechon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40(18):2013-22.
    12. Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 May 12;S1470-2045(21)00094-2.
    13. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-35.
    Published March 20, 2023
  • The Efficacy of First-Line Carboplatin in Metastatic Urothelial Carcinoma - Expert Commentary

    The choice of first-line treatment is particularly crucial for patients with advanced or metastatic urothelial carcinoma (AMUC), as only 15-20% of patients receive second-line treatment due to poor survival. Mori et al. recently re-evaluated the efficacy of carboplatin as a first-line treatment in patients with AMUC by conducting a meta-analysis.
    Published May 11, 2023
  • The Efficacy of Immunotherapy and Carboplatin-Based Chemotherapy in Cisplatin-Ineligible Metastatic Urothelial Cancer Patients - Expert Commentary

    The optimal treatment for patients with metastatic urothelial carcinoma (mUC) patients who are unfit to receive the standard cisplatin-based chemotherapy is uncertain.

    A new study published by Feld et al. in European Urology1 compared the outcomes of carboplatin-based chemotherapy versus immunotherapy. The investigators used the Flatiron Health electronic health record–derived database to find patients with mUC who started first line of treatment. The study included 1530 mUC patients who received carboplatin-based treatment and 487 mUC patients who received immunotherapy between 2011 and 2018. The investigators compared the overall survival (OS) at 12 months and 36 months between the treatment groups. They used propensity score–based inverse probability of treatment weighting (IPTW) to adjust for confounding factors that could affect clinical outcomes.

    The investigators found that, at 12 months, the IPTW-adjusted OS of the immunotherapy group was lower than chemotherapy group (39.6% [95% confidence interval {CI} 34.0–45.3%] versus 46.1% [95% CI 43.4–48.8%]). On the other hand, at 36 months, the IPTW-adjusted OS of the immunotherapy group was higher than chemotherapy group (28.3% [95% CI 21.8–34.7%] vs. 13.3% [95% CI 11.1–15.5%]). Although immunotherapy showed higher hazard of death (HR 1.37, 95% CI 1.15–1.62, p < 0.001) than chemotherapy during the first 12 months, immunotherapy survival rates improved (HR 0.50, 95% CI 0.30–0.85, p= 0.01) for those who survived the one year after the first line.

    This interesting real-world data show temporal variations in patterns of response to different treatments for mUC patients who are ineligible for cisplatin-based chemotherapy. Prospective randomized trials comparing carboplatin-based treatment versus immunotherapy in this patient population is needed to validate this data. Pre-specified analyses should be planned to examine whether specific patient subgroups derive more clinical benefit from chemotherapy or immunotherapy.

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

    Reference: 
    1. Feld, Emily, Joanna Harton, Neal J. Meropol, Blythe JS Adamson, Aaron Cohen, Ravi B. Parikh, Matthew D. Galsky et al. "Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer." European urology (2019).

    Read the Abstract
    Published September 9, 2019
  • The Impact of Bacillus Calmette-Guérin Shortage on Non-Muscle-Invasive Bladder Cancer Patients - Expert Commentary

    A shortage of the Bacillus Calmette-Guérin (BCG) Connaught strain occurred between 2013-2016. A recent paper published by Ourfali et al. in European Urology Focusinvestigated the medical and financial sequelae of BCG shortage on intermediate-risk and high-risk NMIBC patients between 2013 and 2016.
    Published August 8, 2019
  • The Quickly Evolving Treatment Landscape of Metastatic Urothelial Carcinoma: A New Standard of Care in First-Line Systemic Therapy

    Introduction

    Metastatic urothelial carcinoma is associated with a poor prognosis, with an estimated 17,000 deaths annually in the United States from this disease.1 Platinum-based chemotherapy had long been considered the standard of care first line treatment for platinum-eligible patients with metastatic urothelial carcinoma.
    Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
    References:
    1. American Cancer Society. Key Statistics for Bladder Cancer. Accessed on February 26, 2024.
    2. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
    3. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
    4. Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7): 931-945.
    5. Galsky MD, Arija JAA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236): 1547-1557.
    6. Powles TB, Perez Calderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Annal Oncol. 2023;34(Suppl 2): S1340.
    7. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023;389(19): 1778-1779.
    8. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer.  Accessed on February 26, 2024.
    9. U.S. Food and Drug Administration Accepts for Priority Review Bristol Myers Squibb’s Application for Opdivo (nivolumab) in Combination with Cisplatin-Based Chemotherapy for the First-Line Treatment of Adult Patients with Unresectable or Metastatic Urothelial Carcinoma. Accessed on February 26, 2024.U.S. Food and Drug Administration Accepts for Priority Review Bristol Myers Squibb’s Application for Opdivo (nivolumab) in Combination with Cisplatin-Based Chemotherapy for the First-Line Treatment of Adult Patients with Unresectable or Metastatic Urothelial Carcinoma. Accessed on February 26, 2024.
    10. Klumper N, Ralser DJ, Ellinger J, et al. Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance. Clin Cancer Res. 2023;29(8): 1496-1505.
    11. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021;384: 1125-35.
    12. 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.
    13. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29: 2432-2438.
    14. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133: 403-407.
    15. Sternberg CN, Yagoda A, Scher HI, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer. 1989;64: 2448-2458.
    16. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17: 3173-3181.
    17. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42: 50-54.
    18. Lee YS, Ha MS, Tae JH, et al. Gemcitabine-cisplatin versus MVAC chemotherapy for urothelial carcinoma: a nationwide cohort study. Sci Rep. 2023;13: 3682.
    19. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
    20. Powles T, Park SH, Caserta C, et al. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023;41: 3486-3492.
    21. Powles T, Sridhar SS, Loriot Y, et al. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat Med. 2021;27: 2200-2211
    Published March 13, 2024
  • The Significance of Persistent Muscle Invasive After Neoadjuvant Chemotherapy - Expert Commentary

    Downstaging of muscle-invasive bladder cancer (MIBC) following neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) has been correlated with higher survival rates.  
    Published October 8, 2018
  • The Treatment Landscape of Metastatic Urothelial Carcinoma: First-Line Systemic Therapy in Cisplatin Eligible Patients

    Introduction


    Metastatic urothelial carcinoma is associated with a poor prognosis, with a median overall survival of less than two years. To date, combination platinum-based chemotherapy remains the standard of care first line treatment for these patients who are suitable for chemotherapy. This Center of Excellence article will assess criteria for determining cisplatin chemotherapy eligibility, review the landmark trials that established cisplatin-based chemotherapy as the standard of care for first-line treatment, and review recent data for avelumab maintenance therapy among patients that did not progress on first-line chemotherapy.
    Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
    References:
    1. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29: 2432-2438.
    2. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133: 403-407.
    3. Sternberg CN, Yagoda A, Scher HI, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer. 1989;64: 2448-2458.
    4. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17: 3173-3181.
    5. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
    6. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
    7. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42: 50-54.
    8. Lee YS, Ha MS, Tae JH, et al. Gemcitabine-cisplatin versus MVAC chemotherapy for urothelial carcinoma: a nationwide cohort study. Sci Rep. 2023;13: 3682.
    9. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
    10. Powles T, Park SH, Caserta C, et al. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After >/=2 Years of Follow-Up. J Clin Oncol. 2023;41: 3486-3492.
    11. Powles T, Sridhar SS, Loriot Y, et al. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat Med. 2021;27: 2200-2211.
    Published August 29, 2023

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