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Feature: Updates in Bladder Cancer

Lindsey Chippendale
PGY2 Hematology/Oncology Pharmacy Resident at Penn Medicine, University of Pennsylvania Health System
Philadelphia, Pennsylvania

Bladder cancer, or urothelial carcinoma, is the sixth most common cancer diagnosis in the United States with an estimated 83,730 new cases and 17,200 deaths in 2021. There is a 77.1% 5-year relative survival in patients diagnosed with urothelial carcinoma.1 Metastatic urothelial carcinoma has a 5-year overall survival rate of 18%.2 Transitional cell carcinoma is the most common bladder cancer histology, accounting for 90% of all bladder cancers. 1 About 5% of urothelial carcinomas are upper tract which are tumors that develop in the renal pelvis or in the ureter.3

Current Guideline Recommendations:
In muscle-invasive bladder cancer (MIBC) stages two and three, treatment consists of neoadjuvant cisplatin-based combination chemotherapy including gemcitabine and cisplatin or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (DDMVAC) with radical cystectomy, cystectomy alone, or chemoradiotherapy, depending on the performance status of the patient and tolerability of chemotherapy.4

First-line therapy for metastatic disease is dependent upon if the patient is cisplatin eligible. If cisplatin-eligible, the preferred regimen would consist of the same cisplatin-based chemotherapy regimens used for neoadjuvant therapy. If cisplatin-ineligible, the recommended first-line therapy is platinum-based chemotherapy with gemcitabine and carboplatin. An alternative first-line option for cisplatin-ineligible patients is immunotherapy for patients with programmed death-ligand 1 (PD-L1) expression or patients who are not eligible for any platinum-containing chemotherapy.5

A significant number of metastatic patients are unable to tolerate cisplatin therapy due to comorbidities including renal dysfunction or poor performance status.6 This represents a need for less toxic therapies to improve survival rates. Here we will discuss emerging data for systemic therapy in urothelial carcinoma including chemotherapy, immunotherapy, targeted therapy, and antibody drug conjugates.

Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma (UTUC):
Platinum-based chemotherapy including gemcitabine in combination with either cisplatin or carboplatin can be considered for UTUC if neoadjuvant therapy was not given (National Comprehensive Cancer Network (NCCN) Category 2A).

Platinum-based chemotherapy is an option based on POUT, a phase III, randomized, parallel group trial that compared adjuvant platinum-based chemotherapy to surveillance in patients with pT2- 4, Nany or pTany, N1-3, non-metastatic UTUC after nephroureterectomy. Patients received four 21-day cycles of gemcitabine (1,000 mg/ m2) days 1 and 8 of each cycle in combination with cisplatin (70 mg/m2) or carboplatin (AUC 4.5 or 5) on day 1. The primary endpoint of disease-free survival was estimated to be 71% in the chemotherapy cohort and 46% with surveillance (P=0.001) at 3 years. Acute treatment-emergent adverse events > grade 3 were reported for 44% of patients who received chemotherapy versus 4% with surveillance. In the chemotherapy group, there was a greater incidence of > grade 3 decrease in neutrophils (36%), decrease in platelet count (10%), febrile neutropenia (6%), vomiting (6%), and nausea (6%).7

Nivolumab for Adjuvant Therapy:
Nivolumab is an anti-PD-1 monoclonal antibody that is FDA approved for adjuvant therapy following resection in urothelial carcinoma. In bladder cancer, the PD-1 receptor is expressed and is a potential therapeutic target. However, for this indication there is no required testing for PD-1 expression. Anti-PD-1 antibodies inhibit the PD-1 pathway and stimulate the immune system to produce antitumor effects.8 Nivolumab can be considered for use as an “other recommended regimen” (NCCN category 2A) for adjuvant systemic therapy in patients with high-risk pathology after cystectomy regardless if cisplatin-based neoadjuvant therapy was given. High risk was defined as pathological stage of pT3, pT4a, or pN+ and patient ineligible for or declined adjuvant cisplatin-based chemotherapy and who had not received neoadjuvant cisplatin-based chemotherapy, or pathological stage ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin.

Nivolumab is approved for this indication based on CheckMate 247, a phase III, randomized, parallel group clinical trial comparing nivolumab 240 mg intravenously (IV) versus placebo every two weeks for up to one year in patients with MIBC that had received radical surgery. Nivolumab was assessed in patients who had received neoadjuvant therapy as well as in those who had not received neoadjuvant therapy. The primary endpoint showed statistically significantly improved disease-free survival with nivolumab at 20.8 months compared to placebo at 10.8 months (P<0.001), regardless of PD-L1 expression. The most common adverse events were pruritus 23.1%, fatigue 17.4%, and diarrhea 16.8%.9

Erdafitinib
Erdafitinib is a tyrosine kinase inhibitor that inhibits fibroblast growth factor receptor (FRGR) 1 through 4 signaling and is FDA approved for locally advanced or metastatic urothelial carcinoma.10 FGFR mutations occur in 20% of the metastatic urothelial carcinoma patient population.11 Mutations in FGFR contribute to unregulated cell proliferation and oncogenesis. Erdafitinib is indicated for patients who have progressed during or after platinum-based chemotherapy and whose tumors have susceptible FGFR3 or FGFR2 genetic alterations. Erdafitinib is included in the NCCN guidelines as a category 2A recommendation.

Erdafitinib is approved based on the BLC2001 trial. This was an open-label, single arm, phase II study that assessed the use of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma with at least one FGFR3 mutation or FGFR2/3 fusion.

Patients received erdafitinib 8 mg by mouth once daily with or without food. If serum phosphate levels were < 5.5 mg/dL and the patient was not experiencing any ocular adverse effects or any grade 2 or greater adverse reactions on day 14, the patient increased to 9 mg once daily due to phase I study results showing an improved response rate with this dose. The primary endpoint of confirmed response rate occurred in 40% of patients. Median progression-free survival was 5.5 months, and median overall survival was 13.8 months.12 Adverse events of interest and management are detailed below.

Adverse effects (Package Insert %)

  • Hyperphosphatemia (76%): Restrict phosphate intake to 600-800 mg daily. Monitor phosphate levels monthly. If serum phosphate > 7 mg/dL, consider adding an oral phosphate binder until phosphate returns to < 5.5 mg/dL.
  • Ocular disorders (25%): Advise patients to either use artificial tears or hydrating or lubricating eye gels or ointments every 2 hours while awake to prevent dry eyes. Hold treatment if central serous retinopathy occurs. Permanently discontinue if it does not resolve in 4 weeks or if grade 4. Monitor with monthly ophthalmological examinations during the first 4 months of therapy and every 3 months after.

Clinical Pearl

  • Erdafitinib inhibits FGFR signaling in the renal proximal tubule where it impairs the function of the sodium dependent phosphate co-transporter, inhibiting phosphate reabsorption and leading to hyperphosphatemia.

Enfortumab Vedotin
Enfortumab vedotin (EV) is an antibody drug conjugate (ADC) that is FDA approved for locally advanced or metastatic urothelial carcinoma. EV targets nectin-4, which is a cell-adhesion protein that is located on cell surfaces and is highly expressed in urothelial carcinoma. The human IgG1 antibody enfortumab binds to nectin-4 and is internalized, where monomethyl auristatin E (MMAE), a microtubule-disrupting agent, is then released and induces cell cycle arrest and cell death.13 EV is preferred for the treatment of adult patients who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy (NCCN category 2A for second line therapy, category 1 for subsequent therapy).

The NCCN recommendation for EV is based on the EV-301 open-label, randomized, phase III, parallel group clinical trial comparing EV versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based chemotherapy and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Enfortumab vedotin was administered at 1.25 mg/kg (max of 125 mg for patients >100 kg) of body weight IV infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The chemotherapy cohort received one of the following options: docetaxel, paclitaxel, or vinflunine. EV was statistically significant in the primary and secondary endpoints in improving overall survival with a median of 12.88 months versus 8.97 months (P=0.001) and progression-free survival with a median of 5.55 months versus 3.71 months (P<0.001), respectively. Adverse events in the EV cohort included maculopapular rash, peripheral neuropathy, and hyperglycemia.14 Adverse events of interest and management are detailed below.

Adverse effects (Package Insert %)

  • Hyperglycemia (16%): If blood glucose is >250 mg/dL hold therapy. Grade 3 or 4 hyperglycemia occurred in about 8% of patients, and incidence increased in patients with higher body mass index and higher baseline A1C.
  • Peripheral neuropathy (49%): Consider dose reduction or holding therapy if peripheral neuropathy occurs. Discontinue therapy in patients with grade 3 or greater peripheral neuropathy.
  • Ocular disorders (46%): Ocular adverse events include keratitis, blurred vision, and limbal stem cell deficiency. Consider artificial tears for dry eye prophylaxis. Consider ophthalmologic evaluation, dose reduction, or holding therapy if ocular symptoms occur.
  • Skin reactions (54%): Grade 3 to 4 skin reactions occurred in 10% of patients. Consider topical steroids and antihistamines for treatment. Hold therapy for grade 3 skin reactions and permanently discontinue therapy in patients that have grade 4 or recurrent grade 3 skin reactions.
  • Infusion site extravasation (1.3%): Ensure adequate venous access prior to infusing medication. Monitor for extravasation during administration. Reactions can be delayed, with erythema, swelling, and pain worsening 2 to 7 days after extravasation.

Clinical Pearls

  • Though there is a high incidence of peripheral neuropathy with EV, it is largely reversible. Phase I and II studies had 76% of patients with a peripheral neuropathy adverse reaction return to baseline or grade 1 at last follow up.13
  • In clinical trials, diabetic ketoacidosis (DKA) occurred in patients with and without preexisting diabetes mellitus. Monitor for hyperglycemia and DKA in all patients.
  • Nectin-4 is expressed in the skin, attributing to the skin toxicity effects seen with use of EV.

Sacituzumab Govitecan
Sacituzumab govitecan is an ADC that is FDA approved for locally advanced or metastatic urothelial carcinoma. Sacituzumab govitecan is directed against trophoblast cell surface antigen 2 (Trop- 2). Trop-2 is a transmembrane glycoprotein that is expressed on epithelial cancer cells and stimulates cell proliferation. Sacituzumab govitecan binds to Trop-2 and is internalized, releasing SN-38, a topoisomerase 1 inhibitor, leading to DNA damage and cell death.16 Sacituzumab govitecan is indicated for use as subsequent therapy as an “other recommended regimen” (NCCN category 2A) after treatment with a platinum-based therapy and a checkpoint inhibitor if enfortumab vedotin or erdafitinib are not appropriate for the patient.

Sacituzumab govitecan is approved based on TROPHY-U-01, an open-label, single arm, phase II trial that assessed sacituzumab govitecan in patients with locally advanced, unresectable, or metastatic urothelial carcinoma with disease progression following a platinum-based regimen and checkpoint inhibitor therapy.

Patients received sacituzumab govitecan 10 mg/kg administered as an IV infusion once weekly on days 1 and 8 of a 21-day cycle, and continued treatment until disease progression or unacceptable toxicity. The primary endpoint of overall response rate was 27% with responses lasting for a median of 7.2 months. Secondary endpoints were median progression-free survival (5.4 months), and median overall survival (10.9 months).17 Adverse events of interest and management are detailed below.

Adverse effects (Package Insert %)

  • Neutropenia (61%): Hold therapy for absolute neutrophil count below 1500/mm3 on day 1 of any cycle, neutrophil count below 1000/mm3 on day 8 of any cycle, or for neutropenic fever. Consider dose requirements for neutropenia.
  • Diarrhea (65%): If negative for infectious causes of diarrhea, initiate loperamide 4 mg followed by 2 mg with every episode of diarrhea (maximum 16 mg daily). Consider supportive measures for fluid and electrolyte substitution. If patient has cholinergic response to treatment can provide atropine premedication for subsequent treatments. Hold therapy for grade 3 to 4 diarrhea at time of scheduled treatment and resume when resolved to grade < 1.
  • Hypersensitivity and infusion-related reactions (37%): Reactions typically occur within 24 hours of dose administration. Pre-medicate and have emergency medications to treat infusion-related reactions including anaphylaxis available for immediate use. Permanently discontinue therapy for grade 4 infusion-related reactions.
  • Nausea and vomiting (66%): Hold therapy for grade 3 nausea or grade 3 to 4 vomiting at time of scheduled administration and resume when resolved to grade <1. Ensure patients are provided take-home medications for prevention and treatment of nausea and vomiting.

Clinical Pearls

  • Administer the first infusion over 3 hours. Monitor patient throughout infusion and at least 30 minutes after each dose for infusion-related reactions. For subsequent infusions, administer over 1 to 2 hours if prior infusions were tolerated.
  • Pre-medicate with a two or three drug antiemetic combination to prevent nausea and vomiting and use antipyretics and H1/ H2 antagonists to prevent an infusion related reaction. If a prior infusion-related reaction occurred, use corticosteroids (hydrocortisone 50 mg or equivalent by mouth or IV) for subsequent infusions.
  • SN-38 is an irinotecan metabolite, therefore the adverse event profile of sacituzumab govitecan is similar to irinotecan, including neutropenia and diarrhea.
  • Patients who are homozygous for uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at an increased risk for adverse events including febrile neutropenia, neutropenia, and anemia. In patients with unexpected severe or acute early-onset adverse reactions, this may indicate reduced UGT1A1 enzyme activity. Recommendations are to hold therapy or permanently discontinue based on clinical assessment of observed reactions.

Conclusion
Within the past few years the treatment options for metastatic urothelial carcinoma have expanded greatly. Overall survival rates have extended from 7-10 months to 12-13 months and response rates have doubled from 20% to 40% with these new therapies. FGFR targeted therapy and antibody drug conjugates provide alternative options with different mechanisms of action to utilize in patients with chemotherapy resistance.

Ongoing trials are assessing use of immunotherapy in combination with targeted therapy or chemotherapy. Future treatment strategies may also include incorporation of additional targeted agents including poly ADP-ribose polymerase enzyme inhibitor (PARP) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors, and lean more towards focusing on a personalized targeted approach to treatment in patients with metastatic urothelial carcinoma.2

REFERENCES

  1. SEER Stat Fact Sheets: Bladder Cancer. 2021. https://seer.cancer.gov/statfacts/html/urinb.html.
  2. Mollica V, Rizzo A, Montironi R, et al. Current strategies and novel therapeutic approaches for metastatic urothelial carcinoma. Cancers (Basel). 2020;12(6):1449.
  3. Collà Ruvolo C, Nocera L, Stolzenbach LF, et al. Incidence and survival rates of contemporary patients with invasive upper tract urothelial carcinoma. Eur Urol Oncol. 2021;4(5):792-801.
  4. 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(17):3068-77.
  5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer. V.6.2021, 12/06/21, 2020 National Comprehensive Cancer Network, Inc. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.
  6. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Onco.l 2011;29:2432–38.
  7. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomized controlled trial. Lancet. 2020;395(10232):1268-77.
  8. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12:252–64.
  9. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-14.
  10. Balversa (erdafitinib) [prescribing information]. Horsham, PA: Janssen Products, LP; July 2020.
  11. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15:25-41
  12. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338-48.
  13. Padcev (enfortumab vedotin) [prescribing information]. Northbrook, IL: Astellas Pharma US Inc; July 2021.
  14. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-35.
  15. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol.2019;37:2592-2600.
  16. Trodelvy (sacituzumab govitecan) [prescribing information]. Morris Plains, NJ: Gilead Sciences Inc; October 2021.
  17. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-85.
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