Systemic therapy

With approximately 1150 new cases annually in Switzerland, urothelial carcinoma of the urinary bladder is one of the most common cancers of older age. Particularly in the metastatic setting, it has become after a long lull in therapy. For example, checkpoint inhibitors are now the established standard of care in the second-line setting, and avelumab was recently approved for maintenance therapy in the first-line setting.

With approximately 1150 new cases annually in Switzerland, urothelial carcinoma of the urinary bladder is one of the common cancers of older age [1]. Men are affected in approximately three-quarters of all cases, making urinary bladder cancer the fourth most common tumor in men and the ninth most common tumor in women [2]. In non-muscle-invasive stages, which account for approximately 75% of all bladder cancers, local therapeutic measures such as transurethral bladder resection (TURB) and instillation therapy are the mainstay. If, on the other hand, the tumor is locally advanced or metastatic, systemic neoadjuvant, adjuvant or palliative drug treatment is of great importance. Platinum-based chemotherapy is primarily used, but other substances such as checkpoint inhibitors are also playing an increasing role.

Especially in the metastatic setting, after a long lull, a lot has happened over the last years (Fig. 1) . With the emergence of new therapeutic options, the question of the optimal treatment sequence arises both in metastatic tumors and perioperatively. Based on the current study situation, checkpoint inhibitors are now the established standard of care in the second-line treatment of metastatic urothelial carcinoma. In addition, the checkpoint inhibitor avelumab was recently approved for maintenance therapy. The advancement of this class of compounds in the therapeutic lines increases the need for alternative agents, which are currently being tested in Phase II trials and are expected to be available for use soon.

First-line therapy of metastatic urothelial carcinoma: state of the art.

Since 2001, chemotherapy with Gemci-ta-bin/cisplatin has been the undisputed first-line standard of care for metastatic urothelial carcinoma of the urinary bladder. This regimen replaced the extremely toxic M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) therapy established in 1985 in many countries [3]. Although gemcitabine/cisplatin does not show higher efficacy compared to M-VAC, it shows significantly better tolerability [4].

In recent years, increasing attention has been paid to those patients for whom treatment with cisplatin is unsuitable and who are therefore dependent on alternative therapeutic options. The proportion of these patients is not insignificant, also in view of their often advanced age. In most cases, renal function is a contraindication to cisplatin-based chemotherapy. Other reasons for not using cisplatin include poor general health and unfavorable cardiac conditions (Table 1) [5]. To date, in cisplatin-naïve patients with a good ECOG perfomance status of 0-1, gemcitabine/carboplatin therapy, also platinum-based, is considered the standard of care [6]. This can also be administered in cases of impaired renal function. However, with a median overall survival (OS) of just over 9 months and a median progression-free survival (PFS) of 7.6 months, gemcitabine/carboplatin is less effective than treatment with cisplatin, under which an OS of approximately 14 months can be expected [7].

Accordingly, alternative therapies for cisplatin-naïve patients have recently been investigated, particularly checkpoint inhibitors. Both atezolizumab (IMvigor 210) and pembrolizumab (KEYNOTE-052) monotherapy showed good results in this setting, with response rates between 20% and 30% [8,9]. Median overall survival with atezolizumab was 15.9 months in the single-arm phase II IMvigor-210 trial, and that with pembrolizumab was 11.3 months in the phase II KEYNOTE-052 trial. While atezolizumab and pembrolizumab are approved in the EU for first-line treatment of cisplatin-naïve patients with metastatic urothelial carcinoma based on these results, there are currently no approvals for this indication in Switzerland (Tab. 2). Also, in cases where even carboplatin is no longer an option due to comorbidities, checkpoint inhibitors may be a last resort (Fig. 2).

The role of checkpoint inhibitors

Since 2017, checkpoint inhibitors have played an increasingly important role in systemic therapy for urothelial carcinoma, particularly in the second line of treatment. Prior to this, only one drug treatment option existed after failure of platinum-based chemotherapy with the vinca alkaloid vinflunine. In recent years, nivolumab, atezolizumab, and pembrolizumab have each been approved as second-line monotherapy. In the corresponding studies, objective response rates between 15 and 21% were shown, which can be considered extremely positive in such advanced disease [10–12]. Median overall survival was 8.7 months with nivolumab, 7.9 months with atezolizumab, and 10.3 months with pembrolizumab [10–12]. For comparison, treatment with vinflunine can be expected to result in a median OS of 6.9 months in the metastatic second-line setting [13]. Comparative studies with chemotherapies also suggest a significantly lower toxicity of the checkpoint inhibitors. Based on these findings in recent years, immunotherapy has already displaced chemotherapy in the second-line setting.

The addition of a checkpoint inhibitor to first-line chemotherapy in patients with metastatic urothelial carcinoma of the urinary bladder proved less successful. For example, the IMvigor-130 trial concluded that additional atezolizumab administration failed to statistically significantly increase overall response rate, OS, or PFS [14]. The KEYNOTE-361 study showed a similar picture with the addition of pembrolizumab to first-line treatment [15].

Nevertheless, checkpoint inhibitors are increasingly important in the first-line treatment of metastatic urothelial carcinoma – and in the form of maintenance therapy. For example, the JAVELIN-Bladder 100 trial, presented at the 2020 ASCO Annual Meeting, impressively demonstrated the benefit of avelumab as maintenance therapy after first-line platinum-based treatment [16]. The trial used 1:1 randomization to examine the administration of avelumab compared with best supportive care after traditional chemotherapy. Seven hundred patients who had responded to first-line platinum-based treatment or whose disease was stable were included. Those study participants whose tumors were progressive on chemotherapy were excluded from avelumab treatment. Both PFS and OS showed clear benefits of maintenance therapy with avelumab. The median PFS with avelumab was 3.7 months (95% confidence interval 3.5-5.5), and that without maintenance therapy was 2 months (95% confidence interval 1.9-2.7), hazard ratio 0.62. Under checkpoint inhibitor administration, median OS was 21.4 months (95% confidence interval 18.9-26.1), compared with 14.3 months in the control group (95% confidence interval 12.9-17.9), hazard ratio 0.69. These data are not only promising, but also confirm the previous assumption that survival of about 14 months can be expected after palliative chemotherapy in the metastatic setting. Furthermore, a good response rate of 9.7% was observed in this context. At least transient disease control was evident in 41.1% of cases; this rate was 27.4% in the control arm. Overall, a well-manageable safety profile was reported, which was consistent with older studies of avelumab monotherapy. Treatment had to be discontinued in 11.9% of patients, and approximately half of avelumab-treated study participants experienced adverse events ≥Grade3. No Grade 4 or 5 immune-mediated adverse events occurred. Overall, immune-mediated TRAEs (treatment-related adverse events) were observed in 29.4% of patients in the intervention arm. 9% of patients required steroid therapy to control these. Based on these results, Avelumab has now been approved by Swissmedic as first-line maintenance therapy for patients whose disease has been at least stable on platinum-based chemotherapy. A new first-line standard of care could thus be established for approximately 85% of patients with metastatic urothelial carcinoma of the urinary bladder [4,7,17–19]. In addition to avelumab, other checkpoint inhibitors may be used in this setting in the future. For example, a study exists evaluating pembrolizumab in maintenance therapy with similar results (HCRN GU14-182).

The bottom line is that checkpoint inhibitors are now successfully used in the second-line treatment of metastatic urothelial carcinoma and as first-line maintenance therapy. In contrast, simultaneous administration of a first-line checkpoint inhibitor and primary checkpoint inhibitor therapy showed no benefit. Somewhat more controversial is the use of immunotherapy in the first-line treatment of cisplatin-naïve patients. Although an advantage over gemcitabine/carboplatin was observed in various studies, there is currently no approval in Switzerland for this indication. Current treatment recommendations for metastatic urothelial carcinoma are summarized in Figure 2.

The importance of immunotherapy is also increasing in the perioperative setting, albeit with a still sparse study landscape. Thus, neoadjuvant therapy using checkpoint inhibitors shows at least high pathologic response rates, and survival data are pending. Similarly, nivolumab, a checkpoint inhibitor, may be close to European approval for adjuvant therapy.

Looking to the future: second-line therapy in transition

As immunotherapy moves into earlier and earlier lines of therapy, the question of optimal second-line therapy for metastatic urothelial carcinoma increasingly arises. This is because it is unclear how effective pembrolizumab, atezolizumab, and nivolumab still are when a checkpoint inhibitor is already regularly used for maintenance therapy. Thus, there is a high medical need to develop alternative drug classes for the treatment of metastatic urothelial carcinoma. Currently, the FGFR (fibroblast growth factor receptor) inhibitor Erdafitinib and the antibody-drug conjugates Sacituzumab Govitecan and Enfortumab Vedotin are the main hopefuls for second-line therapy.

Erdafitinib is currently being investigated as the first personalized therapy option in metastatic urothelial carcinoma of the urinary bladder. According to results to date, the objective response rate is over 40% [20]. However, FGFR expression is a prerequisite for therapy, which is present in approximately 10% of patients. Wider use could be made of the antibody-drug conjugates sacituzumab govitecan and enfortumab vedotin, which also have high objective response rates of 31% and 41%, respectively [21,22]. Currently, the first Phase III studies are in the start-up phase. Since enfortumab vedotin is already approved in the U.S., a compassionate use program will soon be launched to make the compound available in Europe as well.

Take-Home Messages

Particularly in metastatic urothelial carcinoma of the urinary bladder, a lot has happened over the last years. Checkpoint inhibitors are now the established standard of care in second-line treatment. In addition, the checkpoint inhibitor avelumab was recently approved for first-line maintenance therapy.
Those patients whose disease does not progress on first-line platinum-based chemotherapy should receive maintenance therapy with avelumab. This affects approximately 85% of patients with metastatic urothelial carcinoma of the urinary bladder.
Gemcitabine/cisplatin remains the first-line therapy of choice for metastatic urothelial carcinoma. Simultaneous administration of a checkpoint inhibitor, in contrast to sequential treatment, does not confer additional benefit.
In cisplatin-naïve patients, chemotherapy using gemcitabine/carboplatin is considered the standard of care. However, checkpoint inhibitors are increasingly used in this setting and have been shown to be more effective in some studies (currently not approved in Switzerland, in the EU only for PD-L1 expression).
With the entry of immunotherapy into earlier lines of therapy, there is a high medical need to develop alternative drug classes for the treatment of metastatic urothelial carcinoma. The FGFR inhibitor Erdafitinib and the antibody-drug conjugates Sacituzumab Govitecan and Enfortumab Vedotin are currently the main hopefuls for second-line therapy.

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