Advancing Treatment for Locally Advanced and Metastatic Urothelial Carcinoma: Adopting Advancements and Navigating Challenges

Bladder cancer ranks worldwide as the ninth most frequently diagnosed cancer, with approximately 614,000 new cases and 220,000 deaths recorded in 2022.¹ It is significantly more prevalent in men than in women, for whom it stands as the sixth most common cancer and the ninth leading cause of cancer-related mortality.¹ It is a heterogeneous disease, with urothelial carcinoma (UC) as its predominant histologic type. In the United States, the median age at diagnosis is 73 years, underscoring its prevalence among older adults who have multiple other co-morbidities.² It is subclassified as upper tract UC, if originating from the pyelocaliceal cavities and ureters, which constitutes ~ 5%-10% of all cases, and lower tract UC, if it originates from the bladder and urethra, accounting for 90%-95% of all cases.² Of all the patients diagnosed with locally advanced or metastatic urothelial carcinoma (la/mUC), only half end up receiving first-line therapy.³ Of the patients who receive first-line therapy, 37.4% end up receiving second-line treatment, and only 11.8% receive third-line treatment.⁴

Until recently, platinum-based therapies were the standard first-line treatment for newly diagnosed la/mUC. This changed on December 15, 2023, with the Food and Drug Administration (FDA) approval of enfortumab vedotin (EV), a nectin-4 directed antibody drug conjugate with monomethyl auristatin E (MMAE) payload in combination with pembrolizumab (P), a programmed cell death protein-1 inhibitor (PD-1), for patients with la/mUC based on the EV-302 study (Figure 1).⁵ In this randomized phase 3 study the combination of EV+P, as compared to platinum based chemotherapies, showed a statistically significant improvement in the progression-free survival (median, 12.5 months vs. 6.3 months; hazard ratio (HR) for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; p<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; HR for death, 0.47; 95% CI, 0.38 to 0.58; p<0.001) in previously untreated patients with la/mUC.⁵ In another phase III study, CheckMate-901, the combination therapy with nivolumab plus gemcitabine-cisplatin resulted in significantly better overall survival in patients with previously untreated advanced UC than gemcitabine-cisplatin alone (median 21.7 months vs 18.9 months, HR for death, 0.78; 95% CI, 0.63 to 0.96; p = 0.02).⁶ More recently, the Phase 3 RC48-C016 (NCT05302284) trial compared the combination of disitamab vedotin (RC 48), a HER2-directed antibody drug conjugate with MMAE payload plus toripalimab, a PD-1 inhibitor, to standard of care chemotherapy as a first-line treatment in patients with HER2-expressing la/mUC tumors. The combination therapy of disitamab vedotin plus toripalimab significantly improved both progression-free survival (median, 13.1 vs. 6.5 months; HR 0.36; 95% CI, 0.28 to 0.46; p<0.001) and overall survival (median, 31.5 vs. 16.9 months; HR 0.54; 95% CI, 0.41 to 0.73; P<0.001) as compared to chemotherapy.⁷ However, in the real world, for the US-based population, EV+P is the preferred front-line option, and its adoption has been rapid. Less than four months after FDA approval, it accounted for 50% of frontline treatment regimens, overtaking platinum-based chemotherapy.⁸

This has also opened the field for the next lines of therapy, as previously EV and P were second and third-line options, which, after approval, have become a combined first-line therapy. At present, platinum-based therapies are recommended as the next line of therapy for most eligible patients. However, large real-world experience in this setting is limited.⁹ Moreover, the role of switch maintenance avelumab in patients after second-line platinum therapies with prior treatment with EV+P is unclear. With the volunteer withdrawal of sacituzumab govitecan after the results of the phase-3 TROPiCS-04 study,¹⁰ subsequent therapies outside of clinical trials are limited to erdafitnib for patients with FGFR3-mutated tumors, trastuzumab deruxtecan for HER2-positive, immunohistochemistry (IHC) 3+ tumors, and single-agent taxanes or gemcitabine.⁹

In the Phase 3 THOR cohort 1 study, erdafitinib was compared to chemotherapy among patients with FGFR-altered mUC whose disease progressed after one or two previous treatments that included a PD-1 axis-directed agent. The study showed that erdafitinib leads to a significantly longer overall survival as compared to chemotherapy (12.1 months vs. 7.8 months; HR for death, 0.64; 95% CI, 0.47 to 0.88; p=0.005).¹¹ Trastuzumab deruxtecan is an antibody-drug conjugate directed towards human epidermal growth factor receptor 2 (HER2) with a topoisomerase I inhibitor payload.¹² It has received accelerated FDA approval for adults with advanced/unresectable HER2-positive (IHC 3+ by gastric assay) solid tumors based on results of DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) studies.¹³ In the IHC 3+ UC cohort, the confirmed objective response rate was 56.3%, with a median progression-free survival and overall survival of 7.4 and 13.4 months, respectively.¹² Fig.1 summarizes the mechanisms of therapies in urothelial cancer.

These dramatic changes in the treatment landscape of UC have made its management quite interesting and challenging in the real world. It is worth noting that more than half of the patients progress from the localized disease. In that setting, they may have received either neoadjuvant dose-dense MVAC (preferred) or gemcitabine with cisplatin or the same in the adjuvant setting (if not received in the neoadjuvant setting).^9,14 If they have high-risk disease (defined as ypT2–ypT4a or ypN+ disease on radical resection if received cisplatin-based chemotherapy in the neoadjuvant setting, or if they have not received cisplatin-based neoadjuvant therapy and have pT3, pT4a, or pN+ disease on radical resection of UC and are unfit or refuse cisplatin-based therapies), then nivolumab is an adjuvant option.¹⁵ Perioperative durvalumab plus neoadjuvant cisplatin with gemcitabine demonstrated superior event-free survival (HR for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; p<0.001 by stratified log-rank test) and overall survival (HR for death, 0.75; 95% CI, 0.59 to 0.93; p = 0.01 by stratified log-rank test)) as compared to neoadjuvant cisplatin with gemcitabine alone and has emerged as another preferred regimen.^9,16 Recently, in the phase 3 KEYNOTE-905/EV-303 study (NCT03924895), perioperative EV+P as compared to control has shown significant improvement in progression-free survival [not reached (NR) vs 15.7 months, HR 0.40, 95% CI 0.28–0.57, one-sided p <0.01), overall survival (NR vs 14.7 months, HR 0.50, 95% CI 0.33–0.74, one-sided p <0.01) and pathological complete response (57.1% vs. 8.6%) in patients with muscle-invasive bladder cancer (MIBC) who were predominantly cisplatin-ineligible.¹⁷ This is the first perioperative regimen to improve outcomes vs radical cystectomy and pelvic lymph node dissection in this setting and is the new standard of care. EV is also being investigated in combination with immune checkpoint inhibitors in other perioperative phase 3 trials, including EV304/KEYNOTE-B15 (NCT04700124) in cisplatin-eligible patients and VOLGA (NCT04960709) in cisplatin-ineligible patients.

These therapies will improve survival outcomes for patients with MIBC. However, when patients with MIBC progress to mUC, many have already received cisplatin-based therapy and/or nivolumab. The effectiveness of EV+P in these patients, as well as the additional benefit of pembrolizumab in PD-1 refractory tumors in this setting, remains unknown. Financial challenges, reimbursements, global approvals, and access to EV+P and other therapies remain a critical unmet need.¹⁸ In many countries, late diagnosis due to misattribution of symptoms to other etiologies, patients' unwillingness for testing, poor access to primary care providers, tertiary care centers, specialists, diagnostic testing, and therapies, and patient perceptions and fears, along with belief in traditional or alternative medicine, may produce further challenges leading to disparity in treatment of la/mUC.¹⁸

Another challenge with EV+P remains with the uncertain duration of treatment. In the EV-302 study, P was given for 35 weeks, while EV had no set limit.⁵ In the EV-302 study, 50% and 21.4% of patients developed any-grade neuropathy and ocular disorders, while 3.6%, 7.7%, and 5% of patients developed grade ≥ 3 neuropathy, maculopapular rash, and hyperglycemia, respectively.⁵ Management of these side effects may sometimes need close collaboration with other specialties, including dermatology, ophthalmology, endocrinology, pain management, and neurology, which may not be readily available at all centers. Therefore, biomarkers are needed to guide therapy duration, avoiding unnecessary treatment and mitigating side effects and financial toxicity. It is worth noting that 30.4% of patients treated with EV+P in the EV-302 trial achieved a confirmed clinical response, and the median duration of response was not reached at 29.1 months of follow-up.¹⁹ These patients may be candidates for treatment de-escalation, and future studies utilizing biomarker-guided de-escalation, such as those involving circulating tumor DNA and imaging, are needed.

With trastuzumab deruxtecan, above mentioned all three trials excluded patients with a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening. In the DESTINY-PanTumor02 trial, adjudicated drug-related events of ILD/pneumonitis occurred in 10.5% of patients, of which 1.1% were fatal.¹² ILD is a boxed warning for trastuzumab deruxtecan.¹³ With erdafitnib, important adverse effects include palmar–plantar erythrodysesthesia syndrome, stomatitis, onycholysis, hyperphosphatemia, and central serous retinopathy.¹¹ Both care providers (nurses, nurse practitioners, oncologists) and patients must be aware of these potential side effects so that they can seek timely intervention to mitigate them.

Resistance to EV+P remains a concern. Multiple studies are evaluating novel agents and combinations such as antibody drug conjugates (ADCs) with topoisomerase-1 inhibitors as payload with nectin-4 antibodies, or combination therapies with EV with ADCs directed towards Trop-2 with topoisomerase-1 inhibitor payloads with or without immune therapies (NCT06465069, NCT06483334, NCT03547973). Novel FGFR3 inhibitors, which may have fewer side effects than pan-FGFR inhibitors like erdafitinib and may have efficacy in erdafitinib-resistant tumors, are in development both as a single agent and in combination with EV+P in clinical trials (NCT05614739). With EV+P reshaping the treatment landscape of UC in MIBC, it will be interesting to know if they recur or progress, who could be eligible for rechallenge with EV+P versus who will benefit from a different regimen.

To summarize, the advent of EV+P has dramatically improved the overall survival of patients with la/mUC. It has also impacted the landscape of therapies in the second and third lines. Access, treatment duration, side effects, especially neuropathy, and resistance remain a matter of concern. There is still a need for biomarker-guided de-escalation therapies and improved combinatorial therapies in the frontline and perioperative settings to achieve better clinical outcomes.

U.S.: reports consultancy to Astellas, AstraZeneca, Adaptimmune, Exelixis, Flatiron Health, Gilead, Imvax, Janssen, Kairos, Pfizer, Seattle Genetics, and Sanofi and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics.

Given my role as editor-in-chief, I had no involvement in the peer review of this article. Full responsibility for the editorial process for this article was delegated to another journal editor.

Z.I.O. does not have any disclosures.

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Concept and design: ZIO, US

Data acquisition: ZIO, US

Data analysis and interpretation: ZIO, US

Drafting of the manuscript: ZIO, US

Critical revision of the manuscript: ZIO, US

All authors (ZIO, US) approved the final version of the manuscript and agree to be accountable for all aspects of the work, in accordance with the International Committee of Medical Journal Editors criteria.

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