CME; cisplatin-ineligible mUC; pembrolizumab; FGFR biomarkers; PD-L1 bladder cancer; FGFR-TKI

State of the Union: Advances in the Management of mUC ECHO

Bladder cancer is the 6th most common cancer in the United States with 83,730 diagnoses and 17,200 deaths projected to occur in 2021 alone.¹ Clinicians face many challenges when optimizing treatments for patients with metastatic urothelial carcinoma (mUC), including advanced age at diagnosis and management of systemic comorbidities. To provide optimal care for these patients, it is imperative that clinicians are up to date on the changing therapeutic landscape so treatment plans can be individualized and patient outcomes improved.  

Bladder cancer can be categorized as non-muscle invasive or muscle invasive, each having its own distinct prognosis and therapeutic treatment options. While most cases are non-muscle-invasive superficial bladder cancer, approximately 25% of patients have muscle-invasive disease, and 5% have metastatic disease at initial diagnosis. Lack of consistent treatment plans, inadequate response to new therapeutics, and complicated patient comorbidities have presented major obstacles for the successful treatment of bladder cancer.

Historically, platinum-based chemotherapy was the only systemic treatment option for patients with locally advanced or metastatic disease; however, the introduction of immune checkpoint inhibitors has rapidly shifted the standard of care options for bladder cancer patients.² Unfortunately, patients often do not adequately respond to checkpoint inhibitor treatment, and new agents are needed to treat those who experience disease progression after treatment.

There has been a rapid explosion in the number of available targets and therapeutic options available to treat mUC patients. The current biomarker targets evaluated in bladder cancer are PD-L1, PD-1, and FGFR, which can be tested at various points in the treatment continuum and are critical to guiding treatment selection.

Other prominent targets in advanced mUC do not need to be tested. These include nectin-4, which is targeted by enfortumab vedotin, and TROP-2, which is targeted by sacituzumab govitecan. Ongoing trials are seeking to determine the utility of these novel therapeutic options for treatment after immune checkpoint inhibitor failure.³

Biomarker Testing in mUC

Biomarker testing helps optimize the selection of therapies for patients with bladder cancer. PD-L1 expression testing is a biomarker test that is primarily restricted to first-line mUC treatment and is used to screen patients who are ineligible for cisplatin-containing chemotherapy. PD-L1 expression testing can be valuable for guiding the selection of either carboplatin-based treatment or first-line immunotherapy. Because single-agent immunotherapy is better than the standard of care in the platinum-refractory setting, PD-L1 expression testing holds little value beyond first-line treatment selection. 

Patients who are positive for PD-L1 expression may be eligible for treatment with pembrolizumab or atezolizumab. Those who do not express or express only low levels of PD-L1 should not be offered first-line immunotherapy and should instead be treated with platinum-based chemotherapy when eligible. 

For patients who are entirely ineligible for platinum-containing therapy, PD-L1 expression testing lacks value altogether. Bladder cancer patients who are elderly and frail with a poor performance status and renal dysfunction are not candidates for multi-agent chemotherapy. In such cases, immunotherapy should be used because it is one of the few available options that is safe for treatment in this population.

The role of FGFR signaling in advanced bladder cancer is still being investigated. FGFR3 is expressed in approximately 20% of urothelial carcinoma specimens and is expressed at a higher rate in non-muscle-invasive disease. Erdafitinib binds and inhibits the enzymatic activity of FGFR and is only indicated for patients with susceptible FGFR3 or FGFR2 genetic alterations.⁴

ASCO 2021 Bladder Cancer Trials

Emerging clinical trial data is crucial to guiding therapeutic selection and improving treatment options for bladder cancer patients. KEYNOTE-052 is an ongoing trial investigating the use of pembrolizumab as monotherapy in platinum-ineligible patients in the first-line setting (Figure 1). Trial results showed an objective response rate of 28.6%, median duration of response of 33.4 months, and overall survival of 11.3 months.⁵ Overall, the objective response rate was 47.3% for patients with CPS ≥10 and 20.7% for patients with a CPS <10; no new safety signals were identified.⁶ These results support the FDA indication for pembrolizumab as a frontline treatment for cisplatin-ineligible patients with locally advanced or mUC.

Cohort A of EV-103 evaluated enfortumab vedotin + pembrolizumab in cisplatin-ineligible patients (Figure 2). Trial data confirmed an objective response rate of 73.3% with a complete response of 17.8%.⁷ At a median follow-up of 24.9 months, the median overall survival was 26.1 months.⁸ Notably, both PD-L1-positive and -negative patients responded to treatment, and no new safety signals were generated.

EV-201 is a phase 2 trial evaluating enfortumab vedotin in cisplatin-ineligible, platinum-naïve patients who were previously treated with an immune checkpoint inhibitor (Figure 3).⁹ The second cohort included 89 patients, and results revealed an objective response rate of 52% with 20% of patients having a complete response.¹⁰ Impressively, patients with hepatic metastases yielded a response rate of 48%, which is higher than has been found in any single-agent or combination therapy to date. The data also showed an impressive overall median survival of 14.7 months with no new safety signals.¹⁰ Additional randomized trials are needed to confirm the role of enfortumab vedotin combined with pembrolizumab in platinum-eligible patients with mUC.

|In the case-based activity, “Demonstrating Application into Clinical Practice in the Management of mUC,” 3 patient cases were discussed.

The first case involved a 68-year-old man who was diagnosed with mUC with lung metastases. He had a creatinine clearance of 65 mL/min and was platinum eligible. He received 6 cycles of gemcitabine + cisplatin, which resulted in a partial response. Clinicians discussed the use of maintenance checkpoint inhibitor therapy after the patient’s initial response, but he chose not to receive further treatment at that time. The patient was monitored with CT scans every 3 to 4 months, and 6 months after the completion of chemotherapy, his disease progressed to his lymph nodes. He was treated with a PD-L1 antibody inhibitor and had a response to therapy that lasted 10 months before progressing to both his liver and lungs.

Prior to the availability of antibody-drug conjugates and molecularly targeted agents, clinicians generally would have counseled this patient for supportive care or hospice due to the lack of treatment options beyond checkpoint blockade. This lack of available third-line treatment options is a critically unmet need for patients with mUC progressing to the liver and lungs.

There are 3 potential FDA-approved treatment options for patients in this situation. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates and require no additional testing. Enfortumab vedotin has demonstrated a survival benefit, and sacituzumab govitecan received accelerated approval based on the TROPHY-U-01 study which showed a 27% response rate.

The third alternatively is erdafitinib, which would be a reasonable option for this patient, although it requires biomarker testing that proves the existence of an activating FGFR alteration. Molecular testing and next-generation sequencing should be considered in this case because the identification of FGFR mutations would help guide treatment decisions.

The second case involved an 81-year-old woman who was initially diagnosed with mUC then presented with metastases to the lymph nodes and lungs. Her comorbidities included COPD and stage 3 chronic kidney disease. The patient received first-line immunotherapy with a PD-1 or PD-L1 antibody, and she tolerated treatment well. She developed mild pruritus, a grade 1-2 skin rash that was treated with topical steroids and antihistamines. She had a partial response that lasted over 12 months; however, 12 months after the partial response her disease progressed, and new liver metastases were discovered. She maintained a reasonable performance status at ECOG PS1 and was interested in receiving additional treatment for her cancer.

This patient is cisplatin ineligible and checkpoint experienced. Enfortumab vedotin was recently approved in this patient population. Data has shown a response rate of 38% in patients with liver metastases who are treated with enfortumab vedotin.¹¹ Due to this, clinicians identified enfortumab vedotin as their first-line therapy choice for this patient. 

Additional agents are also being investigated for their utility in this patient population. FGFR mutational analysis should be performed to determine the eligibility of this patient to receive erdafitinib. Sacituzumab govitecan is also being investigated for its efficacy in this setting.

The third case involved a 72-year-old man who was a former smoker with a LAD stent that was placed 6 years ago for coronary artery disease. The patient presented with gross hematuria and had a creatinine clearance of 55 mL/min. Subsequent evaluation revealed muscle-invasive mUC based on a TURB and CT findings of extensive metastases to the lymph nodes and lungs. His ECOG performance status was 1, and he had no other relevant medical history.

Many treatment options were considered for this patient. Clinicians first discussed the patient’s eligibility for cisplatin-containing chemotherapy, which is typically used because it can improve survival and, in some cases, is associated with cure. Clinicians believed it is likely that this patient could safely receive cisplatin-based treatment and recommended it as the first-line approach.

In this case, it would also be reasonable to check the patient’s PD-L1 status, which would influence decision-making if the patient was deemed cisplatin ineligible. If ineligible, a selection between carboplatin and first-line immunotherapy would need to be made. Regardless of initial treatment choice, if the patient achieved stable disease or better, clinicians discussed the consideration of maintenance immunotherapy following disease control instead of waiting until disease progression occurred.

If TURB tissue demonstrating muscle-invasive disease was present at the time of diagnosis, clinicians believed next-generation sequencing would be appropriate. This information would be useful if there was an FGFR mutation, which would indicate the use of erdafitinib.

Advances in the Management of Metastatic Urothelial Cancer

There are several studies focused on early- and late-stage bladder cancer that could be practice changing in first-line mUC treatment (Figure 4).

EV-103 Cohort K is analyzing the first-line use of enfortumab vedotin + pembrolizumab vs enfortumab vedotin alone for patients with mUC who are ineligible for cisplatin-containing chemotherapy.⁸ This study will promote the understanding of the role of this combination, as well as the contribution from each individual component, and will provide information about the effectiveness of these therapies in the first-line setting and beyond.

EV-302 is a randomized phase 3 trial comparing enfortumab vedotin + pembrolizumab vs carboplatin + gemcitabine or cisplatin alone in previously untreated platinum-eligible patients with locally advanced or metastatic urothelial cancer. This is an exciting study that has the potential to redefine how metastatic disease is treated in the first-line setting.¹²

TROPiCS-04 is evaluating sacituzumab govitecan vs physician’s choice single-agent chemotherapy for third-line treatment after disease progression on platinum-based chemotherapy and immunotherapy.¹³ This study will help determine if sacituzumab govitecan improves survival in the treatment refractory setting. If so, this will be added to our therapeutic armamentarium along with enfortumab vedotin.

Conclusion

Clinicians face many challenges when determining the best treatment options for patients with mUC, including the management of complex patient comorbidities, limited effective treatments, and the lack of consistent treatment plans. Despite advances in available therapeutic options, mUC is often associated with poor outcomes. Many patients fail to achieve remission with either a platinum-based chemotherapy regimen or immunotherapy, indicating a tremendous unmet need for additional targeted agents for the treatment of mUC.

Thankfully, the future of mUC treatment is bright. New agents have shown incredible promise for the treatment of patients with mUC as first-, second-, and third-line approaches. As further exploration reveals new therapeutic targets, the role of biomarker testing is clarified, and available clinical trial data grow, there is hope for improved patient outcomes in the near future.  

Resources

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4. Balversa (erdafitinib). Prescribing information. Janssen Products, LP; 2020. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/BALVERSA-pi.pdf 
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8. ASCO 2021: Study EV-103: update on durability results and long-term outcome of enfortumab vedotin + pembrolizumab in first line locally advanced or metastatic urothelial carcinoma. UroToday.  http://urotoday.com/conference-highlights/asco-2021/asco-2021-bladder-cancer/129947-asco-2021-study-ev-103-update-on-durability-results-and-long-term-outcome-of-enfortumab-vedotin-pembrolizumab-in-first-line-locally-advanced-or-metastatic-urothelial-carcinoma.html
9. A study of enfortumab vedotin for patients with locally advanced or metastatic urothelial bladder cancer (EV-201).ClinicalTrials.gov identifier: NCT03219333. Updated August 11, 2021. http://clinicaltrials.gov/ct2/show/NCT03219333
10. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 Cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(6_suppl):394. doi:10.1200/JCO.2021.39.6_suppl.394
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