Urothelial Carcinoma: Muscle-Invasive and Metastatic Disease
Case Continued
Ten months after his procedure, the patient is found to have prominent retroperitoneal lymphadenopathy and a 1.0-cm liver nodule suspicious for malignancy is noted on surveillance imaging. CT-guided biopsy of the liver reveals high-grade urothelial carcinoma, consistent with both recurrence and distant metastasis. The patient is informed that he needs to resume systemic therapy for recurrent metastatic disease. The options discussed include salvage single-agent chemotherapy with gemcitabine or immunotherapy with pembrolizumab. He elects to move forward with immunotherapy and is scheduled to begin pembrolizumab.
- What other immunotherapies might this patient consider for second-line therapy?
- Is chemotherapy a second-line option for this patient?
Second-Line Therapies and Management of Progressive Disease
Disease progression is unfortunately seen in the majority of cases of advanced urothelial carcinoma.46 New second-line therapies have recently been approved by the FDA in the form of monoclonal antibodies targeting programmed death 1 (PD-1) and a PD-1 ligand (PD-L1) (Figure 3). 
Approval of pembrolizumab, a PD-1 inhibitor, was largely supported by the Keynote-045 trial,47,48 which looked at 542 patients who had progressed or recurred after platinum-based chemotherapy. These patients were randomly assigned to either pembrolizumab or investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine). Patients treated with pembrolizumab had a significantly improved OS (median of 10.3 months versus 7.4 months), but no statistically significant difference in PFS (2.1 months versus 3.3 months). Interestingly, the rate of responses of 12 months or longer was higher with pembrolizumab than with more traditional second-line chemotherapy (68% versus 35%). The strength of this data has led to a category 1 recommendation in the most recent NCCN guidelines.39
The approval of atezolizumab, a PD-L1 inhibitor, as a second-line therapy for advanced urothelial carcinoma is largely supported by data from IMvigor211, a phase 3 trial that studied 931 patients randomly assigned to atezolizumab or investigator’s choice chemotherapy. OS did not differ significantly between patients in the atezolizumab group who had ≥ 5% expression of PD-L1 on tumor-infiltrating immune cells and patients in the chemotherapy group (11.1 months versus 10.6 months), but mean duration of response was longer (15.9 months versus 8.3 months).49 Therapy with atezolizumab had significantly fewer toxicities than chemotherapy (grade 3 or 4 toxicities of 20% versus 43%).
Phase 3 studies of nivolumab (PD-1 inhibitor), avelumab (PD-L1 inhibitor), and durvalumab (PD-L1 inhibitor) have not yet been published. These agents have received accelerated approval, however, as second-line treatment of advanced urothelial carcinoma based on promising data from phase 1 and phase 2 studies.50–52
Second-line chemotherapy is also an option for patients who do not qualify for immunotherapy or who progress during or after immunotherapy. Although there has been a great deal of excitement about new developments with immunotherapy and the survival benefit seen compared to investigator’s choice chemotherapy, the fact remains that most patients do not respond to immunotherapy. Still, some patients do derive benefit from single-agent chemotherapy in the platinum-refractory setting. Options based on primarily single-arm studies include gemcitabine, paclitaxel, docetaxel, pemetrexed, ifosfamide, oxaliplatin, and eribulin (Figure 2). In a randomized phase 3 trial, vinflunine demonstrated an OS benefit in platinum-refractory patients compared to best supportive care; it subsequently received approval by the European Medicines Agency.53 More recently in the phase 3 RANGE trial, docetaxel plus ramucirumab (a monoclonal antibody targeting vascular endothelial growth factor receptor 2) was compared to docetaxel plus placebo and met its primary endpoint of an improvement in PFS (median 4.07 months versus 2.76 months, P = 0.0118).54 OS has not been reported and this regimen has not yet received regulatory approval, however. Unfortunately, trials comparing these regimens are lacking, and response rates and survival remain modest. Clearly, better therapies and biomarkers to help personalize treatment options are needed.
Further investigations are underway with alternative regimens, including but not limited to targeted therapy in the setting of specific genetic and epigenetic alterations. These include mutations affecting tyrosine kinase receptors (eg, RAS/RAF, PI3K, AKT, and mTOR), cell cycle regulators (eg, TP53 or RB1), FGFR3 mutations, PTEN deletions, gene amplifications (eg, FGFR1, CCND1, and MDM2), or changes in genes responsible for chromatin remodeling (eg, UTX, CHD6, or ARID1A). As noted, there is particular excitement regarding FGFR3 inhibitors, which have shown compelling efficacy in phase 1 and 2 single-arm trials. Several agents are being evaluated in randomized trials and represent a potential path to the first targeted therapeutic class with a role in urothelial malignancies.
Surgical resection of metastases may be considered in very select cases.55 Surgery may have a role in limiting metastatic complications and improving cancer control, but this should be discussed at length with the patient using a multidisciplinary approach with careful restaging prior to surgery.
