ONCAlert | Upfront Therapy for mRCC

Selecting and Sequencing Therapy in Advanced Urothelial Carcinoma: Navigating a Dynamic Landscape

Moshe C. Ornstein, MD, MA, and Petros Grivas, MD, PhD
Published Online: Feb 13,2018


Cisplatin-based chemotherapy has been and remains the standard of care in advanced urothelial carcinoma (aUC), and can provide a cure for a small subset of these patients. The clinical challenge in aUC is that most patients who are treated with cisplatin-based chemotherapy will ultimately develop refractory aUC and succumb to their disease. There is also a large cohort of patients who have other comorbidities that deem them ineligible to receive these regimens. Fortunately, since May 2016, 5 checkpoint inhibitors (CPIs) have been approved for the treatment of aUC. The rapid approval of these agents presents the clinician with challenges navigating drug selection and sequence decisions. We present an overview of the data that resulted in the approval of these agents, and present our approach to the treatment of patients with aUC.



Although a substantial percentage of patients with localized urothelial carcinoma (UC) will be cured primarily with local disease control, outcomes for patients with advanced disease remain exceedingly poor. For decades, the standard of care (SOC) for advanced UC (aUC) has been cisplatin-based chemotherapy, which results in a median survival of only approximately 15 months.1 Although 13% to 15% of patients with aUC who are treated with chemotherapy can be cured,2 most patients ultimately die of their disease.

Recently, novel immunotherapy with checkpoint inhibitors (CPIs) that target programmed cell death-1 (PD- 1) and programmed death ligand-1 (PD-L1) on T cells and tumor cells (TCs), respectively, has revolutionized therapy for patients with aUC. Five CPIs (atezolizumab, pembrolizumab, avelumab, durvalumab, and nivolumab) are now approved by the FDA for patients with aUC with relapsed/refractory disease following platinumbased chemotherapy. Similarly, 2 of these CPIs (atezolizumab and pembrolizumab) have also gained approval for patients with aUC who are cisplatin-ineligible.3-8


The approval of multiple agents with similar mechanisms of action presents multiple dilemmas for the physician. Most notably, initial drug choice and sequence of therapies in aUC is vague and demands clarification. In this review, we present an overview of the pivotal trials and data that have resulted in the approval of these agents, and present our algorithmic approach for the treatment of patients with aUC.


A detailed overview of the role and data for chemotherapy in aUC is beyond the scope of this article. However, a brief overview is critical because cisplatin- based chemotherapy remains a cornerstone of therapy for patients with aUC. The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) was the historic SOC regimen in aUC, on the basis of results from a phase III trial that demonstrated improved overall survival (OS) with MVAC compared with cisplatin monotherapy (12.5 vs 8.2 months).9 Given the relative unfavorable toxicity profile of traditional MVAC, efforts were undertaken to develop less-toxic, cisplatin-based combination therapies for patients with aUC.

Multiple phase II trials demonstrated that the combination of gemcitabine plus cisplatin (GC) was better tolerated than and had similar clinical efficacy to MVAC.10,11As such, a phase III trial comparing GC to MVAC in patients with aUC was conducted, with a primary endpoint of demonstrating the superiority of GC to MVAC.1,2 In this trial, 405 patients were randomized in 1:1 fashion to receive either GC or MVAC for a maximum of 6 cycles. The primary objective of OS was similar between the GC and MVAC cohorts (14.0 vs 15.2 months; HR, 1.09 [95% CI, 0.88-1.34]; P = .66), as were the 5-year survival rates (GC,3.0; MVAC, 15.3; P = .53).2 Other efficacy endpoints such as objective response rate (ORR), time to progressive disease, and time-to-treatment failure were also similar between the 2 arms. The toxicity profile favored the GC cohort, in which there was less grade 3/4 neutropenia (71% vs 82%), less neutropenic fever (2% vs 14%), and a lower treatment-related mortality rate (1% vs 3%) compared with the classic MVAC cohort.1 Although the trial was not designed to demonstrate noninferiority of GC compared with MVAC, many clinicians rely on these data to support the use of GC as a standard frontline therapy for aUC, given similar efficacy and less toxicity.

Other methods of improving toxicity of traditional GC and MVAC, in which the same drugs are given on slightly different schedules, have been thoroughly investigated and incorporated into clinical practice.12,13 Perhaps most notable was the introduction of the high-dose-intensity MVAC (HD-MVAC; also known as dose-dense MVAC [dd-MVAC]) regimen, in which patients are treated with MVAC every 2 weeks (standard dosage of each drug) with granulocyte colony-stimulating factor (G-CSF) support instead of the 4-week traditional (classic) MVAC regimen. In an international phase III trial comparing classic MVAC versus HD-MVAC in aUC, patients receiving HD-MVAC had less toxicity, fewer treatment delays, and were able to receive twice the number of cisplatin doses as the classic MVAC cohort, despite being on a 14-day treatment regimen.12 In a long-term follow-up of this study, patients who received HD-MVAC had improved ORR, complete response (CR), and progression-free survival (PFS) compared with those who received classic MVAC.14 Thus, HD-MVAC is a generally accepted standard over the traditional MVAC in this setting.

Despite these dosage and schedule modifications, cisplatin-based chemotherapy remains relatively toxic. A primary challenge, therefore, is determining which patients should be given these chemotherapy regimens. A consensus panel developed guidelines to determine cisplatin eligibility. The consensus guidelines declare a patient as “cisplatin-eligible” if they meet the following criteria: ECOG PS (European Cooperative Oncology Group performance status) 0-1, creatinine clearance (CrCl) ≥60 mL/min, no grade ≥2 peripheral neuropathy, no New York Heart Association Class III/IV heart failure, and no significant hearing loss.15 However, the optimal cutoff of adequate renal function is being discussed, with a number of experts administering cisplatin with CrCl ≥ 50 mL/min, often with “split dose” cisplatin (dose divided over 2 days) in borderline cases, while 24- hour urine can be used in such cases to calculate more accurately CrCl. Given the level I (based on randomized phase III trials) evidence of cisplatinbased chemotherapy in aUC and 5-year survival rates of approximately 15%, patients with aUC who meet the eligibility criteria for cisplatin should thus be treated with either GC or ddMVAC as SOC frontline therapy (Figure).

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Selecting and Sequencing Therapy in Advanced Urothelial Carcinoma: Navigating a Dynamic Landscape
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