Exploring the Role of Chemotherapy and Immunotherapy Combos in Urothelial Carcinoma

Andrea Necchi

Immunotherapy regimens may present the future of bladder cancer, particularly in combination with chemotherapy, according to Andrea Necchi, MD.

“PD-1/PD-L1 immune checkpoint inhibitors have already been approved in the United States and Europe for patients with metastatic urothelial cancer who have failed platinum-based chemotherapy or who are ineligible to receive cisplatin-based chemotherapy. This has given an option to those patients who might benefit from them,” states Necchi.

For example, pembrolizumab (Keytruda) significantly improved overall survival over investigators’ choice of chemotherapy in patients with recurrent advanced urothelial carcinoma, according to results of the Keyote-045 study.

OncLive: Can you please provide an overview of your presentation?

In an interview with OncLive at the 2017 Global Congress on Bladder Cancer, Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy, discusses the current role of immunotherapy and chemotherapy for patients with muscle-invasive bladder cancer.Necchi: We are here at the Global Congress on Bladder Cancer discussing the role of immunotherapy in bladder cancer and comparing immunotherapy to chemotherapy in the neoadjuvant or preoperative setting for patients with muscle-invasive bladder cancer. It is a relatively new field that we are still investigating.

PD-1/PD-L1 immune checkpoint inhibitors have already been approved in the United States and Europe for patients with metastatic urothelial cancer who have failed platinum-based chemotherapy or who are ineligible to receive cisplatin-based chemotherapy. This has given an option to those patients who might benefit from them.

There is evidence of pembrolizumab being compared to chemotherapy in the second-line setting. As a natural evolution of the oncology field across solid tumors, we are moving towards early disease stages. There are many trials that are already running in Europe, as well as the United States, that are enrolling patients with earlier disease stages. Patients with non-muscle invasive disease, bacillus Calmette-Guérin-refractory disease, or even gemcitabine resistance are being investigated in studies of combinations of immunotherapy.

There are trials that are moving on in the adjuvant space after radical cystectomy for muscle invasive tumors. There are at least 3 big randomized studies that are now comparing an immunotherapy of either atezolizumab (Tecentriq), nivolumab (Opdivo), or pembrolizumab after radical cystectomy for high-risk patients, such as patients with a nodal environment after radical cystectomy and neoadjuvant chemotherapy.

Another important focus should be on the role of immunotherapy in the neoadjuvant space. Neoadjuvant chemotherapy is included in the recommendation that is currently used by urologists and medical oncologists. It is a standard of care for patients with muscle invasive bladder cancer to receive cisplatin-based chemotherapy. Despite this data, only 20% to 30% of patients can ultimately receive neoadjuvant chemotherapy for a number of reasons. This has to do with a lot of issues that date back decades ago with separate trials conducted by urologists and medical oncologists.

Systemic chemotherapy improved overall survival compared to cystectomy alone. We are dealing with 6% to 10% of improvement in survival and fewer relapses for patients receiving systemic therapy.

There is the possibility to move the field of immunotherapy forward. There are at least 2 studies running in Europe and other studies running in the United States with immunotherapy in the neoadjuvant space. The first study is running in Milan with pembrolizumab, which includes patients with cisplatin-eligible or -ineligible disease who can receive immunotherapy rather than chemotherapy as a neoadjuvant treatment before cystectomy.

The other study focused on the cisplatin-ineligible population. This study is investigating atezolizumab before a radical cystectomy. The results of this study can provide good evidence to move immunotherapy forward even in this setting. What we are missing is a big phase III study in the neoadjuvant setting combining immunotherapy with cisplatin-based chemotherapy, but that will be the natural next step towards the clinical trials designed in this disease.

In the preoperative space, there are a lot of unanswered questions that deal with the safety of the administration of immunotherapy before cystectomy. We don't yet know the answer. There is also a lack of data in the literature regarding the surgical safety of major surgery after immune-checkpoint inhibitors.

Another issue is the rapid progression of patients while on immunotherapy, which may compromise the possibility for patients to be successfully operated on and to see an advantage with systemic therapy before cystectomy. The safety data results of the combination of immunotherapy with chemotherapy should be better focused from the metastatic studies that are ongoing prior to moving safely to the neoadjuvant setting.

What combination of immunotherapy and chemotherapy do you find the most promising?

What are the main takeaways?

These studies in this field of immunotherapy are revitalizing one of the most important points, which is the collaboration between urologists and medical oncologists. We are here for urologists and medical oncologists to work together, dealing with the same issues on the same patients for one of the first times. The patients will benefit the most from this renewed collaboration. The optimal chemotherapy and immunotherapy combination is still a matter of debate. We don't know whether chemotherapy administered after immunotherapy may provide greater outcomes compared with chemotherapy alone. We have some signals from recently published data in the first-line metastatic setting stating that chemotherapy may show higher response rates after immunotherapy. Unfortunately, we still need more data from phase II and phase III studies in the advanced stages to come to any conclusions. My presentation will focus on the past role of chemotherapy, the issues limiting the necessity of chemotherapy in the neoadjuvant space, and the promise of immunotherapy to improve the use systemic therapy before radical cystectomy. We will hopefully have improved the results by combining immunotherapy in this stage.