197Treatment of Metastatic Bladder Cancer: Chemotherapy and Checkpoint Inhibitors
Please note that due to content overlap, first-line systemic treatment of metastatic bladder cancer was discussed in Chapter 22 on treatment of metastatic urothelial cancer of the upper urinary tract.
SECOND-LINE CHEMOTHERAPY OPTIONS
Second-line chemotherapy options include single agents such as docetaxel, gemcitabine, nab-paclitaxel, pemetrexed, and paclitaxel. Phase 2 trials of these agents demonstrate encouraging overall survival (OS). However, only vinflunine has shown improvement in the second-line setting in a phase 3 trial (1,2) (Table 26.1).
In the few patients who still maintain good organ function and adequate performance status, combination regimens may be considered. One of these combinations is gemcitabine plus paclitaxel. In phase 2 and 3 trials, the overall response rate (ORR) rate ranged from 30% to 70%. The progression free survival (PFS) and OS range from 3.1 to 6.1 months and 8 to 14.4 months, respectively. It is important to realize that in all of these trials it was not clear how many patients had progressed after perioperative therapy for locally advanced disease or first-line therapy in the metastatic setting (1).
Another combination that may be considered is carboplatin plus paclitaxel. In phase 2 trials, the ORR is 16% to 38%. The PFS and OS range from 3.7 to 7.9 months and 6 to 17.3 months, respectively. If patients have demonstrated platinum sensitivity, which some define as relapse more than 6 months from last treatment, then cisplatin-based combination chemotherapy can be considered in the second-line setting. After failure of gemcitabine plus cisplatin (GC) in such patients, standard-dose methotrexate + vinblastine + doxorubicin + cisplatin (sMVAC) has shown ORR of 30%, median PFS of 5.3 months, and median OS of 10.9 months. In a similar population, dose-dense MVAC has shown time to progression (TTP) of 9.6 months and OS of 16.5 months. It is important to note that some patients in these second-line combination studies had locally advanced, unresectable disease (1).
199Cisplatin plus paclitaxel has also been evaluated after progression on GC. Of the patients in this phase 2 study, 39% did not have a response to first-line therapy. In this cohort, the ORR was 36%, median TTP was 6.2 months, and median OS was 10.3 months (3). In the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®), there is no standard second-line regimen after progression on first-line cisplatin-based combination chemotherapy. Any of the previously mentioned treatments could be considered, as could other combination regimens or participation in a clinical trial (4).
CHECKPOINT INHIBITORS IN METASTATIC UROTHELIAL CANCER
Immune checkpoint inhibitors (ICIs) include drugs that inhibit the programmed death-1 (PD-1) receptor or programmed death ligand-1 (PD-L1). Multiple ICIs have been evaluated in clinical trials of patients with metastatic urothelial cancer (UC) (5–9) (Table 26.2). There are now two ICIs approved for use in the second-line setting after progression on platinum-based chemotherapy. These approved ICIs are atezolizumab (a PD-L1 inhibitor) and nivolumab (a PD-1 inhibitor) (4). Approval of other ICIs are likely to come soon.
Pembrolizumab is the only ICI at the time of this publication for which a phase 3 trial comparing it to second line chemotherapy (docetaxel, paclitaxel, or vinflunine) has been completed. Pembrolizumab showed significantly improved ORR (21.1% vs 11.4%) and OS (median 10.3 months vs 7.4 months, hazard ratio [HR] 0.73, P = 0.0002) when compared to chemotherapy. While there were no significant differences in median PFS, 1 year PFS was longer with pembrolizumab at 16.8% vs 6.2% with chemotherapy (6) (Table 26.2). Phase 3 clinical trials are currently examining other ICIs in comparison to second line chemotherapy in metastatic UC and we are eagerly awaiting their results.