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First-Line Treatment of Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: The Pursuit of Improved Outcomes

Jeanny B. Aragon-Ching, MD, FACP, and Petros Grivas, MD, PhD

Dr. Jeanny B. Aragon-Ching is the clinical program director of genitourinary cancers at Inova Schar Cancer Institute and an associate professor of medical education at the University of Virginia School of Medicine. Dr. Aragon-Ching is an associate editor for ASCO Daily News.

Dr. Petros Grivas is a professor and clinical program director of the Genitourinary Cancers Program at the University of Washington. Dr. Grivas is also a professor at the Fred Hutchinson Cancer Center.

Dr. Jeanny B. Aragon-Ching has paid honoraria by Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc, and Pfizer/EMD Serono, currently or during the past 2 years. Dr. Aragon-Ching has been paid for any consulting or advisory role by Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, and Exelixis, currently or during the past 2 years. Dr. Aragon-Ching has been paid to participate in a speakers’ bureau for Astellas Pharma, Astellas Seagen, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics, and Pfizer/EMD Serono, currently or during the past 2 years. Dr. Aragon-Ching has had travel, accommodations, or other expenses paid or reimbursed by Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, and Astellas Pharma, currently or during the past 2 years. Dr. Aragon-Ching has served on the advisory board of Merck, Pfizer/EMD Serono, Immunomedics, Exelixis, Aveo Oncology, and Janssen. Dr. Aragon-Ching serves as an Associate Editor for ASCO Daily News.

Dr. Petros Grivas has been paid for any consulting or advisory role by Merck, Bristol-Myers Squibb, AstraZeneca, EMD Serono, Seattle Genetics, Pfizer, Janssen, Mirati Therapeutics, Exelixis, Roche, Genentech, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC, Regeneron Pharmaceuticals, Astellas Pharma, Guardant Health, Urogen pharma, Gilead Sciences, Silverback Therapeutics, BostonGene, Fresenius Kabi, Lucence Health, PureTech, Aadi Bioscience, BostonGene, CG Oncology Inc., Dyania Health, Genentech/Roche, MSD, Pfizer, PureTech, Seagen, ARS Pharma, and G1 Therapeutics, currently or during the past 2 years. Dr. Grivas’ institution has received research funding from Pfizer, Clovis Oncology, Bavarian Nordic, Bristol-Myers Squibb, Debiopharm Group, Merck, QED Therapeutics, GlaxoSmithKline, Mirati Therapeutics, EMD Serono, G1 Therapeutics, MSD, and Gilead Sciences, currently or within the past 2 years.

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Dr. Jeanny B. Aragon-Ching
Dr. Jeanny B. Aragon-Ching

Key Points:

  • Although cisplatin-based chemotherapy is the default treatment for most types of bladder cancer, nearly one-half of patients with metastatic urothelial carcinoma are cisplatin-ineligible.
  • Emerging alternatives to cisplatin include carboplatin-based regimens, immune checkpoint inhibitors, antibody-drug conjugates, and combinations of these therapies; research on these therapeutics is contributing to an important area of unmet patient need.
  • For the moment, carboplatin-based chemotherapy followed by avelumab switch maintenance remains the standard of care for patients who are cisplatin-ineligible without progression on chemotherapy.

Bladder cancer constitutes the sixth most common cancer in the United States, with a projected rise in incidence in the future. Urothelial carcinoma is the most common histology of the urinary tract, and cisplatin-based chemotherapy (in patients who are fit) constitutes the cornerstone of treatment in most bladder cancer settings, from muscle-invasive to locally advanced, unresectable, and metastatic stages. However, multiple factors affect the ability to safely receive cisplatin, including comorbidities such as renal insufficiency, grade ≥ 2 neuropathy or hearing loss, symptomatic heart failure, and ECOG performance status (PS) ≥ 2 in a predominantly older population, all of which may render patients cisplatin-ineligible.1,2 Unfortunately, up to one-half of patients with metastatic urothelial carcinoma may meet at least one of these criteria for cisplatin ineligibility.3

Unfortunately, up to one-half of patients with metastatic urothelial carcinoma may meet the criteria for cisplatin ineligibility.

Alternatives to Cisplatin

Carboplatin (based regimens have historically been the first-line (first-line) treatment of choice for patients who are cisplatin-ineligible, yielding response rates of around 42%, but the response duration is typically short. The gemcitabine/carboplatin combination has seemingly performed better in more contemporary trials such as KEYNOTE-361, IMvigor-130, and DANUBE.4-7 The JAVELIN Bladder-100 phase 3 trial established switch maintenance avelumab as the standard of care after achieving response or stable disease with 4 to 6 cycles of platinum-based chemotherapy (gemcitabine plus either cisplatin or carboplatin) in the overall population (regardless of PD-L1 status).8 Further subgroup analyses showed significant overall survival benefit with avelumab regardless of cisplatin or carboplatin receipt or the attainment of complete or partial response versus stable disease with chemotherapy.8 Gemcitabine/carboplatin was given to about 40% of patients in the JAVELIN Bladder-100 trial.

Dr. Petros Grivas
Dr. Petros Grivas

On the other hand, first-line immune checkpoint inhibitors (ICIs; eg, pembrolizumab and atezolizumab) have been used as single agents, with early phase 2 trials showing response rates in the 23% to 29% range, with notable durable responses.9,10 Based on the results of the phase 3 randomized KEYNOTE-361 and IMvigor-130 trials comparing chemotherapy to ICIs or their combination, the U.S. Food and Drug Administration (FDA) limited the approval of atezolizumab initially only to patients who are cisplatin-ineligible and have PD-L1–positive tumors (Ventana SP142 assay) and to the platinum-ineligible population, although most recently voluntarily withdrawn by drug manufacturer given failure to meet the co-primary endpoint of overall survival; meanwhile, pembrolizumab is FDA-approved only in patients who are platinum-ineligible regardless of PD-L1 status. The term “patients who are platinum-ineligible” has not been well-defined until recently, and now involves meeting 1 of the following 5 consensus-based parameters to be considered “platinum-ineligible”: ECOG PS ≥ 3; creatinine clearance < 30 ml/min; peripheral neuropathy ≥ grade 2; New York Heart Association Heart Failure Class ≥ 3; and/or ECOG PS 2 and creatinine clearance < 30 ml/min.11

State of the Field

The first-line therapy option for patients who are cisplatin-ineligible remains an important area of unmet need. In addition, therapy attrition rates have been high in metastatic urothelial cancer, in which up to 23% of patients may not be able to receive upfront therapy and up to 67% may never receive second-line treatment, suggesting that the first-line treatment to control the disease really matters.12 However, the advent of more effective therapeutic options in the salvage setting, including ICIs, antibody-drug conjugates, and FGFR inhibitors, may have been improving this attrition.

Table. Selected Trials Including Patients Who Are Cisplatin-Ineligible Selected Trials Including Patients Who Are Cisplatin-Ineligible
Abbreviations: AE, adverse events; APF12, alive and progression-free survival at 12 months; BICR, blinded independent central review; cis-eligible, cisplatin-eligible; cis-ineligible, cisplatin-ineligible; DCR, disease control rate; Dom, domvanalimab; DOR, duration of response; durva, durvalumab; EORTC, European Organization for Research and Treatment of Care; EV, enfortumab vedotin; Gem/carbo, gemcitabine/carboplatin; Gem/cis, gemcitabine/cisplatin; Nivo, nivolumab; Nivo/ipi, nivolumab and ipilimumab; N, number; ORR, overall response rate; OS, overall survival; Pembro, pembrolizumab; PFS, progression-free survival; PKs, pharmacokinetics; SG, sacituzumab govitecan; treme, tremelimumab; ZIM, zimberelimab.View larger

Recently, data on first-line therapy with enfortumab vedotin (EV) plus pembrolizumab in a phase 1b/2 trial that included 45 patients showed a promising confirmed objective response rate (ORR) of 73.3%, with a complete response rate of 15.6%.13 In addition, results from cohort K of the EV-103 study (NCT03288545) were recently reported, with 76 patients treated with the EV/pembrolizumab combination showing an impressive ORR of 64.5% (95% CI [52.7, 75.1]), short median time to response, and a median response duration that was not reached. Treatment-related adverse events (TRAEs) are worthy of mention and require very close monitoring given that about one-half of patients had any-grade skin rash and/or peripheral neuropathy; overall, about two-thirds of patients experienced grade ≥ 3 TRAEs, with 3 therapy-related deaths. However, it is worth noting that the trial was not adequately powered to compare EV alone against EV/pembrolizumab. The ongoing EV-302 phase 3 randomized trial of EV/pembrolizumab vs gemcitabine/platinum may provide a more definitive answer about the optimal first-line therapy. The proportion of patients who are cisplatin-eligible who actually receive cisplatin and of patients whose cancer does not progress on chemotherapy and who receive switch maintenance avelumab will be very important to review once data are reported.13

Further strategies remain important to improve outcomes in the first-line setting for patients who are cisplatin-ineligible. Although multiple attempts at improving outcomes in this setting with other combination therapies have been made, none have been very successful, including the olaparib and durvalumab combination (BAYOU) and the addition of lenvatinib to pembrolizumab, which did not meet its coprimary endpoints of progression-free survival and overall survival in the LEAP-011 randomized phase 3 trial.14,15 In addition, efforts to improve the first-line treatment outcomes with ICI-based therapy alone in the CheckMate-901 trial failed to meet the primary endpoint of overall survival with ipilimumab/nivolumab versus chemotherapy for patients whose tumors expressed PD-L1 ≥ 1%, although evaluation of those who are cisplatin-ineligible and from other subsets is still ongoing.16 Additional targeted therapy with erdafitinib alone or in combination with cetrelimab, an anti–PD-1 agent, resulted in an ORR of 33% with erdafitinib monotherapy (18 patients) and 68% with the combination therapy (19 patients).17 There are a plethora of ongoing trials including patients who are cisplatin-ineligible in the first-line setting (eg, NILE, MAINCAV, Medley, PRESERVE-3, and Trophy-U01 cohort 6; Table). In addition, emerging data on the use of vaccines, as seen in CV301 with atezolizumab, were reported, although the trial was halted for futility.18 Moreover, robust and systematic correlative analysis is important for the discovery and validation of biomarkers that may potentially have clinical utility in the future.19


To conclude, baseline patient and cancer characteristics, toxicity and efficacy data, level of evidence, patient preferences, frequency of visits and therapy burden, clinician familiarity with the regimen, guidelines, and regulatory decisions can all impact potential therapy selection in patients who are cisplatin-ineligible. For the moment, carboplatin-based chemotherapy followed by avelumab switch maintenance remains the standard of care for patients who are cisplatin-ineligible, but carboplatin-eligible, without progression on chemotherapy.


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  3. Parikh RB, Feld EK, Galsky MD, et al. First-line immune checkpoint inhibitor use in cisplatinplatin-eligible patients with advanced urothelial carcinoma: A secular trend analysis. Future Oncol. 2020;16(2):4341-4345.
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  6. Galsky MD, Arija JAA, Bamias A, et al; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557.
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  8. Grivas P, Park SH, Voog E, et al. 704MO Avelumab first-line (first-line) maintenance + best supportive care (BSC) vs BSC alone with first-line chemotherapy (CTx) for advanced urothelial carcinoma (UC): Subgroup analyses from JAVELIN Bladder 100. Ann Oncol. 2020;31(suppl 4):S555-S556.
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  16. Bristol Myers Squibb. Bristol Myers Squibb provides update on CheckMate-901 trial evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) as first-line treatment of patients with unresectable or metastatic urothelial carcinoma. Accessed November 28, 2022.
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