Novel Targeted and Immunotherapeutic Agents Reshape Metastatic Urothelial Cancer Landscape

Treatment options for patients with metastatic urothelial cancer have rapidly expanded as FDA approvals of immunotherapeutics push the boundaries of a once stagnant treatment landscape. Combination regimens and the addition of targeted approaches, further demonstrate progress in areas that have been tough to crack.

Daniel P. Petrylak, MD

Daniel P. Petrylak, MD

Treatment options for patients with metastatic urothelial cancer have rapidly expanded as FDA approvals of immunotherapeutics push the boundaries of a once stagnant treatment landscape. Combination regimens and the addition of targeted approaches, including the pan-FGFR tyrosine kinase inhibitor erdafitinib (Balversa), further demonstrate progress in areas that have been tough to crack, according to Daniel P. Petrylak, MD, who presented an overview of the field during New York GU: 14th Annual Interdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies.1

Although predictive biomarkers remain an unmet clinical need in the treatment of patients with metastatic urothelial cancer, studies evaluating the combination of checkpoint inhibition with targeted therapies, as well as results from basket trials comprising patients with metastatic urothelial cancer may help investigators overcome these hurdles.1,2 Patients have continued to benefit from maintenance therapies utilizing immune checkpoint inhibitors (ICIs); however, recent data reviews have led to restricted labels and more critical FDA oversight as confirmatory data becomes available.

FGFR: A Promising Target

FGFR3 expression is detected in 10%-20% of patients,” said Petrylak, a professor of medicine and urology, director of Genitourinary Translational Working Group, and codirector of the Signal Transduction Program at Smillow Cancer Center, Yale University in New Haven, Connecticut. “The drug that goes along with that expression is erdafitinib.”

The FDA granted accelerated approval to erdafitinib in April 2019 for the treatment of adult patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration who have progressed on platinum-containing chemotherapy.3 The approval was based on the results of the phase 2 BLC2001 study (NCT02365597), which examined the agent in patients with metastatic or surgically unresectable, locally advanced urothelial carcinoma.4

Patients who received erdafitinib achieved an ORR of 40.4% (n = 40; 95% CI, 30.7%-50.1%), a median time to response of 1.4 months, and a median duration of response (DOR) of 5.6 months (95% CI, 4.2-7.2). Additionally, patients achieved a median PFS of 5.5 months (95% CI, 4.2-6.0), as well as a median OS of 13.8 months (95% CI, 9.8-not estimable [NE]). At a follow-up of 11 months, 21.2% of patients continued to receive treatment with erdafitinib.

ICIs May Require a Closer Look

Approved ICIs such as pembrolizumab (Keytruda; approved in May 2017), nivolumab (Opdivo; approved in February 2017), and most recently, avelumab (Bavencio), have all made headway as treatment options for patients with metastatic urothelial cancer. Although these options remain on the market, the FDA has restricted the use of both pembrolizumab and atezolizumab (Tecentriq) after follow-up data failed to support initial findings.5

In July 2018, the FDA issued an alert notifying the community that patients who had PD-L1–low disease as specified by the threshold of the trials had decreased survival compared with patients who had received chemotherapy. As a result of this alert, the phase 3 KEYNOTE-361 trial (NCT02853305), examining the use of pembrolizumab with or without platinum-based chemotherapy, and the phase 3 IMvigor-130 (NCT02807636), which looked at atezolizumab (Tecentriq) with or without platinum-based chemotherapy in patients with untreated, locally advance or metastatic disease, stopped enrolling patients who were PD-L1 low in the monotherapy arms.5 The FDA updated the prescribing information for both drugs to require use of an FDA-approved test for selection of patients being treated in the first-line setting who are cisplatin-ineligible.

Other accelerated approvals are following a similar pattern in metastatic urothelial cancer with additional indications for the 2 agents set to be reviewed as part of a 3-day public hearing by FDA Oncologic Drugs Advisory Committee scheduled for April 27 to 29.

Most recently, the developers of atezolizumab and durvalumab voluntarily withdrew indications based on confirmatory trial results not demonstration significant improvements in overall survival (OS). Roche voluntarily withdrew the indication for atezolizumab in patients with prior-platinum-treated metastatic urothelial carcinoma following the release of results of the phase 3 IMvigor211 trial (NCT02302807).6

Similarly, AstraZeneca, the developer of the ICI durvalumab (Imfinzi), voluntarily withdrawn the FDA indication for the agent’s use in previously treated patients with locally advanced or metastatic bladder cancer. This decision followed the release of results of the confirmatory trial DANUBE (NCT02516241) which failed to meet both primary end points.7

Maintenance Immunotherapeutics for PD-L1–Positive Patients

Despite the turnover in accelerated approvals, avelumab has carved out a role as a maintenance therapy for patients based on results of the phase 3 JAVELIN Bladder 100 trial (NCT02603432). Investigators enrolled patients with unresectable, locally advanced or metastatic disease who had achieved a complete response (CR), partial response (PR), or stable disease from 4-6 cycles of first-line cisplatin plus gemcitabine or carboplatin plus gemcitabine.8 Patients were randomized to receive either avelumab plus best supportive care or best supportive care alone. Notably, 55% of patients in the overall population and 47% of patients who were PD-L1 positive had visceral metastases at baseline across all arms of the study.

In the overall patient population, avelumab arm achieved a median overall survival (OS) of 21.4 months (95% CI, 18.9-26.1) compared with 14.3 months in the best supportive care arm (95% CI, 12.9-17.9; HR, 0.69; 95% CI, 0.56-0.86; P < .001). In the PD-L1–positive patient population, the avelumab arm’s median OS was not estimable (NE; 95% CI, 20.3-NE) vs 17.1 months (95% CI, 13.5-23.7) in the best supportive care arm.

According the authors of the study, an OS benefit was observed across all subgroups included in the study. Additionally, the regimen helped to improve median progression-free survival (PFS) in the avelumab arm (3.7 months; 95% CI, 3.5-5.5) vs the best supportive care arm (2.0 months; 95% CI, 1.9-2.7; HR, 0.62; 95% CI, 0.52-0.75; P < .001).

However, investigators noted that avelumab yielded a low overall response rate (ORR) in both the overall population (9.7%; 95% CI, 6.8%-13.1%) and the PD-L1–positive population (13.8%; 95% CI, 9.2%-19.5%).

Of the patients who discontinued treatment with avelumab in both the overall and PD-L1–positive populations and received a subsequent treatment, 6.3% and 9.0%, respectively, were given a PD-1 or PD-L1 inhibitor.

ADCs Make Their Mark

Petrylak discussed 2 antibody-drug conjugates (ADCs)—enfortumab vedotin-ejfv (Padcev) and sacituzumab govitecan-hziy (Trodelvy)—which investigators have observed promising efficacy data. “In phase 2 and 3 [studies, enfortumab vedotin] and sacituzumab govitecan in phase 2 [studies] have promising activity in patients who have [progressed on] 2 or more prior lines of therapy,” Petrylak said. “Enfortumab vedotin has accelerated approval and we hope that the FDA will grant a full approval this year.”

Enfortumab vedotin was granted an accelerated approval by the FDA in December 2019 for patients with advanced or metastatic urothelial carcinoma based on the results of the phase 2 EV-201 trial (NCT032193333).9,10 Patients who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy experienced an ORR of 44% (35.1%-53.2%), including a CR rate of 12% and a PR rate of 32%.

According to the authors of the study, similar responses were observed across all patient subgroups, including those with liver metastases and patients who have not experienced a response to prior PD-1 and PD-L1 therapies. Notably, patients who had received prior ICIs had a confirmed CR rate of 3.4%, a confirmed PR rate of 37%, and an ORR of 40% (95% CI, 30.2%-51.4%). Patients also achieved a disease control rate of 74% (95% CI, 63.8%-82.9%).

In the ongoing second cohort, which had received a PD-1 or PD-L1 therapy while being platinum chemotherapy–naïve and cisplatin ineligible, investigators reported an ORR of 52.0% (95% CI, 40.8%-62.4%), including a confirmed CR rate of 20.0% and a confirmed PR rate of 31.0%. The median time to response was 1.8 months (IQR, 1.7-1.9) and the median DOR at 11 months was 10.9 months. Lastly, investigators reported a median PFS of 5.8 months (95% CI, 5.03-8.28) and a median OS of 14.7 months (95% CI, 10.51-18.20).

The agent was most recently examined in the phase 1b EV-103 trial (NCT02091999), which treated patients with locally advanced or metastatic disease with a first-line combination of pembrolizumab and enfortumab vedotin.11 The combination regimen achieved a confirmed ORR of 73.3% (95% CI, 58.1%-85.4%); the CR rate was 15.6% and the PR rate was 57.8%.

Additionally, 93% of patients experienced reduction of tumor size from baseline. A median PFS of 12.3 months (95% CI, 7.98-NE) and a 12-month PFS rate of 50.1% were noted by investigators. The median OS was not reached and a 12-month OS rate of 81.6% (95% CI, 62.0%-91.8%) was observed. After a median follow-up of 10.4 months, the median DOR has not been reached and a 12-month DOR rate of 53.7% was observed (range, 1.2-12.9 months). Of the 33 patients who responded to treatment, 55% had an ongoing response, 33% had progressive disease or died, and 12% started a new antitumor treatment prior to developing progressive disease.

Lastly, sacituzumab govitecan was given a fast-track designation by the FDA in April 2020 based on the results of the phase 2 TROPHY-U-01 trial (NCT03547973) for adult patients with locally advanced or metastatic urothelial cancer who had received a prior PD-1/PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.12,13 Initial findings demonstrated that after a median follow-up of 4.1 months, patients had an ORR of 29% (95% CI, 15%-46%), including a CR of 6% and a PR of 17%. Additionally, 8 of 10 responders continued to experience an ongoing response at the time of data cutoff.

The study’s final results indicated that after a median follow-up of 6.8 months, patients had an ORR of 29%, consisting entirely of PRs. The median time to response was 1.3 months (range, 1.1-1.5 months) with a median DOR that was not reached (4.3 months-not reached). Of the 6 responders, 5 continue to experience an ongoing response. In total, 62% of patients experienced a reduction in tumor size.

Although investigators explain that the follow-up is still early, median PFS and OS associated with sacituzumab govitecan compared favorably with other standards of care in the space for patients with platinum-ineligible metastatic disease who have progressed on a previous ICIs. The median PFS was 5.50 months (95% CI, 1.70-7.30) and the median OS was 11.10 months (95% CI, 4.90 months-not available). Additionally, the OS rate was 76.4% (95% CI, 48.4%-90.5%) at 6 months and 43.0% (95% CI, 13.1%-70.4%) at 12 months.


  1. Petrylak DP. Metastatic bladder cancer: immunologic and targeted approaches. Presented at New York GU 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 12-13, 2021; virtual. Accessed March 12, 2021.
  2. Mendiratta P, Grivas P. Emerging biomarkers and targeted therapies in urothelial carcinoma Ann Transl Med. 2018;6(12):250. doi:10.21037/atm.2018.05.49
  3. Balversa. Prescribing Information. FDA; 2019. Accessed March 12, 2021.
  4. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381:338-348. doi:10.1056/NEJMoa1817323
  5. FDA alerts health care professionals and oncology clinical investigators about an efficacy issue identified in clinical trials for some patients taking Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as monotherapy to treat urothelial cancer with low expression of PD-L1. News release. FDA. August 16, 2018. Accessed March 12, 2021.
  6. Roche provides update on Tecentriq US indication in prior-platinum treated metastatic bladder cancer. News release. Roche. March 8, 2021. Accessed March 12, 2021.
  7. Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. News release. AstraZeneca. February 22, 2021. Accessed March 12, 2021.

  8. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18). doi:10.1200/JCO.2020.38.18_suppl.LBA1
  9. Seagen and Astellas announce submission of two supplemental biologics license applications to the US FDA for PADCEV (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer. News release. Seagen Inc. February 18, 2021. Accessed March 12, 2021.
  10. 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(29):2592-2600. doi:10.1200/JCO.19.01140
  11. Hoimes CJ, Rosenberg JE, Petrylak DP, et al. Abstract A23: the EV-103 trial: enfortumab vedotin plus pembrolizumab and/or chemotherapy for patients with locally advanced or metastatic urothelial cancer. Clin Can Res. 2020;26(15 supp):A23. doi:10.1158/1557-3265.BLADDER19-A23.
  12. Tagawa ST, Balar A, Petrylak DP, et al. Initial results from TROPHY-U-01: a phase 2 open-label study of sacituzumab govitecan in patients (pts) with metastatic urothelial cancer (mUC) after failure of platinum-based regimens (PLT) or immunotherapy. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394
  13. Loriot Y, Balar AV, Petrylak DP, et al. TROPHY-U-01 cohort 1 final results: a phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Accessed March 12, 2021. LBA24.
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