An Immunotherapy–Chemotherapy Combination Opens a New Chapter in Bladder Cancer Treatment

Bladder cancer is the most common cancer of the urinary tract. At diagnosis or during follow-up, 25% of patients have developed metastases (spread through the body). For patients with advanced bladder cancer of this kind, the standard initial treatment approach is systemic chemotherapy. Unfortunately, despite the multiple chemotherapy options available, median survival in these patients is around 15 months. Another important problem in bladder cancer is that accompanying illnesses prevent approximately 50% of patients from receiving the desired effective chemotherapy.

Immunotherapies are drugs that have demonstrated efficacy in many cancer types, particularly in patients with bladder cancer who cannot receive chemotherapy. Among these agents, atezolizumab (Tecentriq) and pembrolizumab (keytruda) have entered clinical use for patients unable to receive a chemotherapy regimen containing cisplatin, as first-line treatment in those positive for the PD-L1 immunotherapy marker, with approval from both the US drug agency (FDA) and the European Medicines Agency (EMA). How to further improve the efficacy of these clinically used immunotherapies is one of today's most important research questions.

That chemotherapy improves the efficacy of immunotherapy has been demonstrated in previous studies. As a result, the combined use of immunotherapy and chemotherapy has now become a first-line treatment option in lung cancer for patients with suitable performance status. Two studies evaluating the same efficacy in urinary tract cancers have attracted attention in oncology.

2 Recent Studies Evaluating Immunotherapy Plus Chemotherapy in Bladder Cancer

The IMvigor130 Study

The first study evaluated the efficacy of chemotherapy and immunotherapy in previously untreated stage 4 transitional epithelial-cell cancers of the urinary tract (bladder, ureter and renal pelvis). It was IMvigor130, a phase-III clinical trial.

The study enrolled 1213 patients from 35 countries. Of these patients, 50% were unable to receive cisplatin-containing chemotherapy. The trial was planned with three arms:

1. Cisplatin or carboplatin plus gemcitabine plus atezolizumab immunotherapy,
2. Atezolizumab alone,
3. The two-drug chemotherapy regimen of cisplatin or carboplatin plus gemcitabine.

Results

• Adding immunotherapy to chemotherapy improved the time until the patients' disease worsened, known as progression-free survival (PFS), by an additional 2 months (8 months versus 6 months). Overall survival was an additional 2.6 months longer (16 months versus 13.4 months).
• Analysis of patient subgroups showed that, regardless of PD-L1 level, the combination was more effective particularly in patients able to receive cisplatin-containing chemotherapy as the regimen added to immunotherapy.
• Compared with chemotherapy alone, chemotherapy plus immunotherapy showed no difference in adverse events or treatment discontinuation because of adverse events.

In conclusion, the IMvigor130 study established the atezolizumab–chemotherapy combination as one of the treatment protocols that can be considered for previously untreated patients with metastatic urinary tract cancers, particularly those with suitable overall performance status who can receive cisplatin.

A Phase-II Study of Pembrolizumab Plus nab-paklitaksel

The second study investigated previously platinum-treated patients with metastatic urinary tract cancers, combining nab-paklitaxel chemotherapy with the immunotherapy agent pembrolizumab in a phase II study. The trial included 70 patients who had previously received platinum-containing chemotherapy.

• The overall response rate achieved with Nab-paklitaksel plus pembrolizumab was 40%. A complete response was achieved in 14% of patients.
• The median time until disease progression (PFS) was 5 months.
• This benefit was found to be independent of PD-L1 or tumor mutational burden, which are important biomarkers for immunotherapy.
• In terms of adverse events, nab-pakltaxel chemotherapy caused grade 1 and 2 neuropathy (nerve damage), but no other serious adverse events were observed.

In conclusion, the combined use of immunotherapy and chemotherapy appears likely to become standard first-line treatment for bladder cancer soon. It is therefore unclear what role nab-paklitaksel and pembrolizumab will have in second-line treatment in the future. This study suggests that the Nab-paclitaxel pembrolizumab combination is more effective than standard treatments as second-line therapy in patients who have not previously received immunotherapy.