Considerations in prescribing pharmacotherapy for localized and metastatic urothelial carcinoma

KEYWORDS:

• Urothelial cancer
• chemotherapy
• immunotherapy
• antibody-drug conjugates
• targeted therapy

1. Introduction

While the majority of urothelial cancers are localized in nature, metastatic urothelial carcinoma has a generally poor prognosis, with a 5-year survival rate of ~5%. Historically, cytotoxic chemotherapy was the only therapeutic modality available for the treatment of advanced disease but over the past few years, several new agents have received regulatory approval. As a result, awareness of the nuances in selecting between and sequencing therapies is needed.

2. Therapy for metastatic disease

2.1. Platinum-based chemotherapy

The therapeutic paradigm for advanced urothelial carcinoma has changed significantly over the past few years with the approval of several new therapies. Nevertheless, first-line therapy remains platinum-based chemotherapy in most instances, with both GC and MVAC exhibiting similar efficacy (median survival ~15 months) and potential for durable survival (~15%), although GC is associated with lower toxicity and better quality of life [1]. Fitness for cisplatin is the primary consideration when approaching a newly-diagnosed patient with advanced urothelial carcinoma, with cisplatin-based chemotherapy preferred in those who are cisplatin eligible. A significant proportion of patients are ineligible for cisplatin owing to one of the following criteria: ECOG performance status ≥2, eGFR <60 ml/min, Grade ≥2 hearing loss, Grade ≥2 neuropathy, and NYHA Class ≥3 heart failure [2]. In those who are not cisplatin eligible, substitution with carboplatin (combined with gemcitabine) has traditionally been the treatment of choice. However, recent results from trials evaluating pembrolizumab and atezolizumab in the first-line setting have challenged this.

2.2. Immune checkpoint inhibitors

Immune checkpoint inhibitors were initially developed in the post-platinum setting. Five PD-(L)1 inhibitors (pembrolizumab, atezolizumab, avelumab, durvalumab, and nivolumab) have been approved for patients who have had prior platinum-based therapy. These agents yield responses in 15% to 20% of patients. However, only pembrolizumab has demonstrated an overall survival benefit compared to second-line chemotherapy in a phase 3 trial [3].

Pembrolizumab [4] and atezolizumab [5] have also shown durable responses in 20–30% of unselected patients in phase 2 trials in the first-line, cisplatin-ineligible setting. Trials evaluating these agents in the front-line setting (regardless of cisplatin eligibility) are ongoing (IMvigor130, KEYNOTE-361), with results from the former showing a significant (albeit modest) benefit in progression-free survival, but not overall survival, with the addition of atezolizumab to platinum-based chemotherapy compared to platinum-based chemotherapy alone [6]. A recent press release on KEYNOTE-361 reported that there was not a significant improvement in outcomes with the addition of pembrolizumab to platinum-based chemotherapy [7]. Data reviewed by the Data Safety Committees of both studies have suggested that patients receiving single-agent atezolizumab or pembrolizumab who have low PD-L1 expression have poorer outcomes compared to those receiving cisplatin- or carboplatin-based chemotherapy, which has led to a change in the regulatory labels. Therefore, assessment of PD-L1 expression is critical when selecting first-line therapy, with cisplatin-based chemotherapy recommended for those who are eligible. Patients who are cisplatin-ineligible and have low tumor PD-L1 expression should receive a carboplatin-based regimen, while carboplatin-based chemotherapy, pembrolizumab and atezolizumab are valid options in patients who have high PD-L1 expression. Pembrolizumab or atezolizumab are also FDA approved as first-line therapy in patients who are not eligible for any platinum-based chemotherapy regardless of PD-L1 status; however, in clinical practice, factors such as poor performance status or comorbidities that may preclude the use of carboplatin-based chemotherapy may generally also preclude the use of PD-(L)1 inhibitors.

Recently, data from the JAVELIN Bladder 100 trial of switch-maintenance avelumab (compared to best supportive care) in patients without progression after 4–6 cycles of first-line platinum-based chemotherapy were presented and showed a significant 7-month improvement in median overall survival [8], results which should be considered practice-changing. However, it is worth noting that the benefit appeared more pronounced in patients with higher PD-L1 expression, although a significant survival benefit was seen in all patients, regardless of PD-L1 expression. Crossover was also not mandated on study and only ~40% of patients who progressed in the observation arm received subsequent anti-PD-(L)1 therapy. A significant proportion of patients with metastatic urothelial cancer do not receive subsequent lines of therapy owing to rapid progression, comorbidity, or poor performance status, suggesting that the major impact of this paradigm may be to ensure early delivery of second-line immunotherapy. Conversely, some patients who have complete response to cisplatin-based chemotherapy are potentially cured and may be ‘over-treated’ by a switch-maintenance approach.

2.3. Other salvage therapies

Aside from chemo- and immunotherapies, two other agents are currently approved in urothelial carcinoma. Erdafitinib, an oral FGFR1-4 inhibitor, is approved after prior platinum-based therapy in the 10–20% of patients who have FGFR3 mutations or FGFR2/3 fusions on the basis of a phase 2 trial demonstrating a response rate of 40% [9]. In that trial, 22 patients had received a prior immune checkpoint inhibitor; of these, 13 responded to erdafinib while only 1 had responded to prior immunotherapy. This suggests that response to an FGFR inhibitor was unaffected by prior use of immune checkpoint inhibitors, but that patients with FGFR alterations may respond poorly to immunotherapy. However, post hoc analyses from the IMVigor 210 and CheckMate 275 phase 2 trials evaluating single-agent atezolizumab and nivolumab, respectively, in the post-platinum setting have shown that response rates to atezolizumab or nivolumab were similar (~20%) in patients with and without FGFR3 mutations [10].

More recently, enfortumab vedotin (EV), an antibody-drug conjugate targeting nectin-4 (which is ubiquitously expressed in urothelial carcinoma), produced a 44% response rate in patients who had received prior platinum and immunotherapy [11], and EV has received accelerated approved in this setting. Trials evaluating EV with chemo- and immunotherapy in earlier disease settings are ongoing. It is important to note that that EV is effectively a targeted cytotoxic agent and may cause neuropathy and myelosuppression; hence, it is important to consider the patient’s fitness for therapy, particularly if they have baseline neuropathy from prior cisplatin use.

3. Therapy for localized disease

The recommended management of locally advanced resectable muscle-invasive bladder carcinoma (MIBC) is neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC). In eligible patients, 3–4 cycles of therapy are usually given prior to RC, and though only the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen is supported by prospective phase III trial data [12], dose-dense MVAC and gemcitabine-cisplatin (GC) are also widely used in clinical practice. In cisplatin-eligible patients who have undergone upfront RC and have high risk ≥pT3 or node-positive disease, it is reasonable to offer adjuvant cisplatin-based combination chemotherapy based on meta-analyses of randomized studies [13]. Patients who are cisplatin-ineligible should proceed to upfront RC and enrollment on adjuvant therapy trials should be considered.

Neoadjuvant chemotherapy has frequently been applied to high-risk cisplatin-eligible upper-tract urothelial carcinoma (UTUC), by extrapolating from MIBC data, but the difficulty of definitive pre-operative staging precludes the optimal selection of patients for NAC. Recent data from the POUT trial showed a significant benefit in disease-free survival with the use of adjuvant platinum-based chemotherapy (gemcitabine and cisplatin or carboplatin) after surgery for ≥pT2 or node-positive UTUC [14]. However, the decline in renal function following nephroureterectomy may render many patients ineligible for optimal cisplatin-based adjuvant chemotherapy.

4. Expert opinion

The key considerations when choosing therapy for urothelial carcinoma include eligibility for cisplatin, fitness for carboplatin, PD-L1 status (accepting the heterogeneity in measuring this in clinical practice), candidacy for immune checkpoint blockade (i.e. active autoimmune disease or use of high doses of steroids), and the presence of FGFR2/3 alterations in the tumor.

Within this context, a major emerging controversy is the treatment of patients with metastatic disease who are cisplatin-ineligible but have high PD-L1 expression, specifically the choice of first-line anti-PD-(L)1 versus the JAVELIN Bladder 100 approach of first-line carboplatin-gemcitabine for 4–6 cycles followed by maintenance avelumab in those who do not progress. It is noteworthy that there are no phase 3 data showing a survival benefit with first-line PD-(L)1 blockade; indeed, phase 3 trials evaluating the combination of a PD-(L)1 inhibitor with gemcitabine-platinum or CTLA-4 inhibitor have not demonstrated improved survival compared to gemcitabine-platinum chemotherapy alone [6,15]. Another approach being tested is dual VEGF and PD-1 inhibition in the LEAP trial, which is comparing the combination of lenvatinib and pembrolizumab with pembrolizumab alone in cisplatin-ineligible/PD-L1 high or platinum-ineligible patients.

Preliminary data from the EV and pembrolizumab combination in first-line cisplatin-ineligible patients showed a response rate of 73%, including 16% with complete response, with the caveat of a small phase 1b/2 trial [16]. The ongoing EV-302 phase 3 trial is evaluating this combination, alone or with platinum, versus standard platinum-based chemotherapy. However, the EV-302 trial does not deliver switch-maintenance PD-(L)1 inhibitor in the control arm, and it is unclear if the combination of EV with pembrolizumab, with or without platinum, will out-perform the JAVELIN Bladder 100 paradigm. While novel combinations are undergoing evaluation in the first-line setting, it is also important to conduct studies assessing the sequencing of available agents. In particular, the optimal sequencing of erdafitinib, immunotherapy, and EV remains to be determined in patients with FGFR2/3 alterations. Moreover, combinations of these agents may warrant evaluation, given the difficulty of delivering multiple lines of therapy for this aggressive disease.

In the localized disease setting, there are data emerging for the use of neoadjuvant PD-(L)1 inhibition, with or without chemotherapy [17], and phase 3 trials evaluating this strategy are underway. In contrast, there was no benefit seen with adjuvant atezolizumab in patients who underwent surgery for high muscle-invasive urothelial carcinoma, with or without neoadjuvant chemotherapy [18]. Nevertheless, we await data from other adjuvant immunotherapy trials and the ongoing PROOF-302 phase 3 trial that is evaluating adjuvant infigratinib, an FGFR inhibitor, in patients with FGFR3 alterations.

In summary, clinicians should be aware of various nuances, including fitness for therapy, PD-L1 status, and FGFR2/3 status, when determining treatment selection for patients with urothelial carcinoma. It is highly likely that the therapeutic landscape for urothelial carcinoma will evolve over the next few years when results of trials exploring combinations of therapies as well as newer agents become available. Given the rapid pace of drug development in this disease, enrollment on a clinical trial, where available, should be the preferred option when treating a patient with urothelial carcinoma.

Declaration of interest

GP Sonpavde has served on advisory boards for Pfizer, Bristol-Myers Squibb, Genentech, EMD Serono, Novartis, Merck & Co, Sanofi, Seattle Genetics/Astellas, AstraZeneca, Exelixis, Janssen, Amgen, Eisai and Bicycle Therapeutics. He has also received research support via his institution from Boehringer Ingelheim, Bayer, Pfizer, Merck & Co, Sanofi, and AstraZeneca. Furthermore, GP Sonpavde has been provided with travel fees from Bristol-Myers Squibb and AstraZeneca and Speaking fees from the Physicians Education Resource (PER), Onclive, Research to Practice and Clinical Care Options. In addition, GP Sonpavde has received writing fees from UpToDate and has served on Steering committees of trials for Bristol-Myers Squibb, Bavarian Nordic, Seattle Genetics and QED (all unpaid) as well as AstraZeneca and Debiopharm (both paid). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.