Evolving Standards of Care in the Systemic Treatment of Metastatic Urothelial Cancer

As of 2024, bladder cancer is the sixth most common cancer diagnosis in adults in the United States.¹ It is more common in men than women and primarily affects persons above the age of 55 years.² The National Cancer Institute estimates that more than 16,000 Americans will die of bladder cancer in 2024, with more than 90% of bladder cancers in Europe and the United States being of urothelial histology.^2,3 Treatment of urothelial cancer can differ dramatically between early stage localized disease and locally advanced or metastatic disease, and there are different roles for surgery, radiation, and locally administered or systemic antineoplastic treatments based on the stage of diagnosis, as well as patient goals, preferences, performance status, organ function, and other medical comorbidities.⁴

Systemic conventional cytotoxic chemotherapy, more specifically platinum-containing chemotherapy, has been the standard of care first-line treatment in eligible patients with locally advanced/metastatic urothelial cancer (LA/mUC) for decades.⁴ Cisplatin eligibility has been studied and defined to aid decision-making for selection of treatment.⁵ Subsequent therapies after first-line treatment historically have included other cytotoxic chemotherapy.^4,6 Novel mechanisms of action beyond traditional cytotoxic chemotherapy have been developed and studied, including small-molecule targeted inhibitors, immunotherapy, antibody drug conjugates (ADCs), or combinations of these with chemotherapy. As such, the standard of care for initial and subsequent management of this disease has changed rapidly in recent years.

This review will discuss the recent evolution in the treatment of LA/mUC, novel therapies and regimens including their role in treatment of the disease and considerations for pharmacists and other clinicians when managing these patients.

Image Credit: © MP-AI - stock.adobe.com

Erdafitinib

Erdafitinib (Balversa; Janssen Biotech, Inc)is a pan-fibroblast growth factor receptor (FGFR) inhibitor currently indicated for the treatment of LA/mUC with susceptible FGFR3 genetic alterations that has progressed following at least 1 prior systemic therapy.⁷ Erdafitinib was initially approved through the FDA’s accelerated approval program in 2019 for patients with LA/mUC harboring either FGFR2 or FGFR3 mutation or fusion/rearrangement based on the high overall response rate (ORR) from the single arm phase 2, open-label BLC2001 trial.^8,9 Results from cohort 1 of the confirmatory phase 3 THOR trial (NCT03390504) demonstrated the significant overall survival (OS) and progression-free survival (PFS) benefit of erdafitinib vs docetaxel or vinflunine chemotherapy, specifically in patients who had received prior anti–programmed cell death protein 1 (PD-1) or anti–programmed death ligand 1 (PD-L1) agents.¹⁰ For this reason, the FDA approval currently does not recommend erdafitinib be used prior to PD-1/PD-L1 inhibitors if patients are eligible to receive them.⁷ Cohort 2 of the THOR trial randomized PD-1/PD-L1-naive patients to receive erdafitinib or pembrolizumab and reported no statistically significant difference in OS, so it remains to be seen if the FDA will revise its approval of erdafitinib.¹¹ Based on cohort 1 of the THOR trial, the full approval of erdafitinib is limited to FGFR3 alterations only.⁷

Erdafitinib has a unique dose titration owing to the pharmacodynamic effect on serum phosphate levels.⁷ Patients are started at 8 mg once daily and phosphate level should be measured 14 to 21 days after therapy initiation.⁷ The dose should be increased to 9 mg once daily if phosphate level is less than 9.0 mg/dL and there are no ocular disorders or grade 2 or greater adverse effects (AEs).⁷ Additionally, the dose should be reduced by increments of 1 mg per reduction with available pill sizes to a minimum of 4 mg daily for AEs requiring dose modification.⁷ Severe AEs occurred in 45% of patients treated with erdafitinib in the THOR trial, the most common being palmar–plantar erythrodysesthesia syndrome (9.6%), stomatitis (8.1%), onycholysis (5.9%), and hyperphosphatemia (5.2%).¹⁰ Patients should receive routine ophthalmological examinations at baseline and during therapy, and should be counseled to report vision changes to detect and intervene on ocular disorders including central serous retinopathy/retinal pigment epithelial detachment.⁷

A nutritionist or dietician may help optimize patients’ diets if hyperphosphatemia occurs. Erdafitinib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C9 and is an inhibitor of P-glycoprotein.⁷

Immune Checkpoint Inhibitors

Antibody inhibitors of PD-1 or PD-L1 are collectively known as immune checkpoint inhibitors (ICI) due to their mechanism of inducing T cell recognition and destruction of cancerous cells.¹² Currently, nivolumab (Opdivo; Bristol Myers Squibb), avelumab (Bavencio; EMD Serono), and pembrolizumab (Keytruda; Merck & Co, Inc) are approved for use in metastatic urothelial cancer. They are each approved as single-agent treatment following progression during or following platinum-containing chemotherapy, but this review will discuss newer approvals and advancements of using ICI in metastatic UC specifically, such as combination treatment or maintenance. Each agent has a specific dose and frequency of administration that should be adhered to; dose hold/delay or discontinuation may occur, but no dose reduction is allowed. Weight-based doses were often used in clinical trials but flat doses regardless of weight are approved for ICIs as well and can be utilized.

AEs of ICIs are distinct from, yet sometimes resemble those of traditional cytotoxic anti-cancer treatments.^13,14 These immunotherapy-related AEs (IrAEs) are currently best understood as a consequence of immune system ‘auto’-reactivity, but mechanisms are complex and not precisely understood.¹⁵ IrAEs are diverse and can affect nearly any organ system in the body, and examples include skin rash (dermatitis), diarrhea (colitis), hypo/hyperthyroidism, laboratory changes suggestive of hepatitis, rarely myocarditis, and numerous others.^13,14 Clinicians should be familiar with ICI and other immunotherapies to manage these IrAEs appropriately. Organizations such as the National Comprehensive Cancer Network, the American Society of Clinical Oncology (ASCO), and Society for Immunotherapy of Cancer have clinician resources for managing IrAEs as well as education resources for patients.^15,16

Avelumab as Maintenance Therapy

Avelumab, a PD-L1 inhibitor, is indicated as switch maintenance treatment for LA/mUC that did not progress on first-line platinum-containing chemotherapy based on the phase 3 JAVELIN Bladder (JB) 100 trial (NCT02603432).^17,18 Patients do not need to have their tumor tested for PD-L1 positivity, microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR), or high tumor mutational burden (TMB) to be eligible for avelumab.¹⁷ Gemcitabine plus cisplatin or carboplatin were given for 4 to 6 cycles as induction platinum-containing chemotherapy in the JB100 trial, though given the relative similar benefit of these regimens when compared to methotrexate, vinblastine, doxorubicin, and cisplatin given in an “accelerated” or “dose-dense” manner, it is appropriate to consider avelumab maintenance treatment following any of the above platinum-containing regimens.^4,18 Avelumab was administered until progression or unacceptable toxicity following completion of 4 to 6 cycles of chemotherapy.18 Due to the risk of infusion reaction, patients should receive an antihistamine and acetaminophen prior to at least the first 4 infusions of avelumab and be monitored closely during the infusion.¹⁷

Nivolumab

Nivolumab, a PD-1 inhibitor, was approved in March 2024 to be given in combination with cisplatin and gemcitabine in cisplatin-eligible patients as first-line treatment of LA/mUC based on the CheckMate 901 trial (NCT03036098).^19,20 CheckMate 901 was a phase 3 open-label trial comparing the addition of nivolumab to cisplatin/gemcitabine against such chemotherapy alone.²⁰ Prior to the CheckMate 901 trial, no novel agent added in concurrent combination to first-line platinum-containing chemotherapy had demonstrated a significant OS benefit, including atezolizumab (IMvigor130 trial [NCT02807636]) or pembrolizumab (KEYNOTE-361 trial [NCT02853305]).^21,22 While nivolumab is given every 21 days to match the 21-day cycle length of cisplatin plus gemcitabine, it can be given every 14 or 28 days as continuation maintenance following completion of chemotherapy until progression or unacceptable toxicity. Patients do not need to have the tumor tested for PD-L1 positivity, MSI-H/dMMR, or high TMB to be eligible.²³ Pre-medications are not routinely recommended upfront, except for those given to prevent AEs from cisplatin and gemcitabine.

Enfortumab Vedotin-efjv

Enfortumab vedotin-efjv (EV, Padcev; Seagen Inc) is the first-in-class and only ADC of the cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) linked to the nectin-4 targeting antibody enfortumab.²⁴ EV first received accelerated approval in 2019 for treatment of mUC that progressed on platinum-containing chemotherapy and PD-1/PD-L1 inhibitor based on the single arm phase 2 EV-201 trial (NCT03219333).^25,26 Further data from a second cohort demonstrated that EV still showed a high ORR in patients who were cisplatin-ineligible; the indication was amended to require progression on only 1 or more prior line of treatment if a patient was cisplatin-ineligible.²⁷ The phase 3 randomized EV-301 trial confirmed the significant OS and PFS benefit of EV monotherapy vs taxane or vinflunine and led to full FDA approval.²⁸ The combination of EV and pembrolizumab has been studied and will be discussed later.

EV is initially dosed at 1.25 mg/kg, capping at 100 kg of body weight, and is reduced stepwise by 0.25 mg/kg per dose level to a minimum of 0.5 mg/kg for adverse effect intolerability.²⁴ As a single agent, it is administered on days 1, 8, and 15 of a 28-day cycle.²⁴ The only recommended initial pre-medications are anti-emetics. Common AEs for EV include skin reactions like maculopapular rash, dry eyes, peripheral sensory neuropathy, and diarrhea.²⁴ Severe skin reaction incidence is more than 10%, and patients with rapidly evolving skin reactions should be evaluated immediately, as potentially fatal Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have occurred, most frequently with the first cycle.²⁴ Pneumonitis/interstitial lung or ocular disorders including vision changes may occur rarely.²⁴ EV should be held if a patient’s labs on the day of infusion show hyperglycemia that’s greater than 250 mg/dL, as diabetic ketoacidosis can develop.²⁴ MMAE is hepatically metabolized by CYP3A4, so extra attention should be given to patients with liver cirrhosis/dysfunction.²⁴

Pembrolizumab and Enfortumab Vedotin-efjv

The combination of pembrolizumab and EV first received accelerated approval in 2023 as initial treatment for LA/mUC in cisplatin-ineligible patients based on positive results from the phase 1b/2 open-label EV-103/KEYNOTE-869 trial.29,30 In late 2023, the landmark phase 3, global, open-label randomized EV-302/KEYNOTE-A39 trial demonstrated a dramatic OS and PFS benefit for patients treated with pembrolizumab-EV as frontline therapy vs platinum (cisplatin or carboplatin) plus gemcitabine.³¹ The FDA approved pembrolizumab-EV as treatment in any patient diagnosed with LA/mUC in late 2023 ahead of the full publication of EV-302/KEYNOTE-A39, and this is considered the preferred frontline regimen in la/mUC.^4,32 These developments represent a major leap forward in the management of LA/mUC and the first time that a non-platinum antineoplastic treatment outperformed platinum-containing chemotherapy in this setting.³¹ However, the OS and PFS benefit from the addition of nivolumab to cisplatin/gemcitabine in CheckMate 901 cannot be directly compared to the results of EV-302/KEYNOTE-A39, so it may still be appropriate to consider platinum-containing chemotherapy for initial management in select patients with concern regarding EV use, or if there is no access to EV + pembrolizumab (outside US).⁴ Individual patient characteristics and patient preferences may also help guide choice of initial therapy.

In combination, pembrolizumab and EV are administered on a 21-day cycle with EV administered on days 1 and 8, and pembrolizumab is given only on day 1 each cycle.²⁴ The only recommended initial pre-medications are anti-emetics, primarily for EV. Due to different anti-cancer mechanisms, clinicians must consider that patients may experience AEs consistent with both EV and pembrolizumab, including potentially overlapping AEs, like skin toxicity, diarrhea, or pneumonitis.²⁴ Higher incidence of certain AEs when compared to single-agent treatment may be seen; peripheral neuropathy is a major reason for EV dose adjustments.²⁴

Sacituzumab Govitecan-hziy

Sacituzumab govitecan-hziy (SG, Trodelvy; Gilead Sciences Inc) is an ADC of the Trop-2-targeting antibody sacituzumab linked to the cytotoxic topoisomerase I inhibitor, SN-38.³³ In 2021, SG currently was granted accelerated approval for LA/mUC that has progressed on platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor based on results from the single arm phase 2 TROPHY-U-01 cohort 1 trial (NCT03547973).^34,35

SG is administered initially at 10 mg/kg on days 1 and 8 of a 21-day cycle until progression or unacceptable toxicity.³⁴ Patients should be pre-medicated with antiemetics, as well as an antipyretic and histamine-1 and histamine-2 antagonists as infusion reactions may occur.³⁴ Corticosteroids can be used as pre-medication for patients who had prior infusion reaction and/or as an antiemetic.³⁴

SN-38 is primarily metabolized by uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), so drug interactions can occur, and some patients are “poor metabolizers” who are at increased risk for hematologic toxicity, diarrhea, and other AEs.³⁴ Testing for UGT1A1 genetic variants is suggested in patients who experience severe AEs, especially early in treatment. Use of granulocyte-colony stimulating factors as primary prophylaxis should be considered to reduce the risk of febrile neutropenia, which occurred in 10% of patients in TROPHY-U-01.³⁵ Dose reduction for intolerable or severe AEs is done by administering dose levels of 7.5 mg/kg or 5 mg/kg.³⁴ Severe diarrhea and hematologic toxicity can occur regardless of UGT1A1 genetic variants, and other AEs include fatigue, alopecia, mucositis, rash, and laboratory abnormalities, such as changes in liver function tests.³⁴

Fam-Trastuzumab Deruxtecan-nxk

Fam-Trastuzumab Deruxtecan-nxk (T-DXd, Enhertu; Daiichi-Sankyo, Inc) is a human epidermal growth factor 2 (HER2)–directed antibody and topoisomerase inhibitor conjugate previously approved for only breast, gastric, and non-small cell lung cancers, but more recently also broadly for treatment of adults with metastatic or unresectable solid tumors that are HER2-positive as determined by a score of 3+ by immunohistochemistry (IHC) and who received 1 or more systemic treatment or are without “satisfactory" alternative treatments.36 This is currently an accelerated approval. The open-label, phase 2 DESTINY-PanTumor02 trial (NCT04482309) demonstrated PFS and OS benefits in patients treated with T-DXd.³⁷ Patients enrolled had a variety of tumors including endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and others, and were stratified according to HER2 expression level (1+, 2+, 3+) as determined by IHC and using ASCO/College of American Pathology guidelines for scoring HER2 in gastric cancer.³⁷ Patients with HER2 3+ expression had the longest median OS benefit.³⁷ T-Dxd may be considered for patients with HER2-positive 3+ LA/mUC after progression on prior treatment, or if they are deemed to have no better alternatives.⁴

For its tumor agnostic indication, T-DXd is dosed initially at 5.4 mg/kg every 21-day cycle.³⁸ Stepwise dose level reductions for toxicities are approved.38 Deruxtecan is primarily metabolized by CYP3A4.38 Left ventricular ejection fraction should be monitored before initiation and periodically during treatment.³⁸ T-DXd is highly emetogenic and patients should receive appropriate anti-emetics prior to and after infusion.³⁸ Other common AEs include diarrhea, fatigue, neutropenia, thrombocytopenia, hair thinning/loss, abdominal pain, musculoskeletal pain, and elevations in aminotransferases.^37,38 Severe interstitial lung disease can occur, so patients should be counseled on risk and presentation, and they should be instructed to immediately report symptoms.³⁸

Conclusion

The landscape for LA/mUC has changed dramatically with the implementation of ICIs and novel targeted therapies. The combination of pembrolizumab/EV is transformative, while other combinations look promising. Ongoing clinical trials continue to explore these anticancer therapies and other novel investigational agents and combinations, and there is optimism that our armamentarium will continue to increase and outcomes to improve.

Acknowledgments

Thank you to Petros Grivas, MD, PhD for review of this article for content accuracy.

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