Next Steps in Bladder Cancer to Include Combination Immunotherapy

Gina Columbus @ginacolumbusonc
Published: Saturday, Nov 18, 2017

David R. Gandara, MD
Andrea Necchi, MD
While the 5 PD-1/PD-L1 inhibitors approved by the FDA in a 2-year span have drastically shifted the therapeutic paradigm of bladder cancer, researchers are already taking the next steps that include combination regimens to have a greater benefit across patient subgroups, according to Andrea Necchi, MD.

The class of agents indicated for the second-line setting includes pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio), yet pembrolizumab remains the sole checkpoint inhibitor to demonstrate an improvement in overall survival (OS) in a phase III study. Each of these inhibitors also elicit responses in approximately 15% to 25% of patients across differing populations.

To take the next step in this research, investigators are now combining immunotherapies together, or with chemotherapy, to create added benefits and more durable, long-lasting responses.

In an interview with OncLive during the 2017 EMUC Congress, Necchi, a medical oncologist at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, discussed the evolution of bladder cancer therapies, the challenge with the currently available agents, and the next steps and clinical trials being conducted in the field.

OncLive: Please provide an overview of your lecture at the 2017 EMUC Congress.

Necchi: I was asked to summarize the revolution of bladder cancer treatment in the advent of immune checkpoint inhibitors. It’s quite an issue because we have achieved multiple results from multiple trials, including the different populations.

The most important message may come from the major clinical trials that have been published in the last year. We have 2 different populations: those who have already received chemotherapy or the first-line, platinum-untreated patients. For the platinum-untreated patients, we had the results of 2 single-agent, single-arm trials with atezolizumab and with pembrolizumab. They were very similar—almost identical—in their design and endpoints, but not identical in the patient population that were included.

Basically, KEYNOTE-052 with pembrolizumab and cohort 1 of IMvigor 210 with atezolizumab led to the same results, meaning there were about 15% to 20% of patients who maintained a long-term response. These are patients benefitting from long-term immunotherapy and may avoid receiving chemotherapy in the long run. In this respect, these 2 trials led to, basically, very similar outcomes.

The other point is related to the population of patients who already received platinum-based chemotherapy. In this context, we have multiple phase II and some phase III trials [read out]. We have pembrolizumab from KEYNOTE-045, whereby pembrolizumab was compared with chemotherapy and showed the level 1 evidence of an improvement in survival compared with chemotherapy in these patients.

We have another phase III study with atezolizumab compared with chemotherapy, which failed to achieve the primary endpoint of OS for PD-L1–positive patients. It was positive for the intent-to-treat, not primary, population. The most important message from both trials…is that we have the possibility for these patients to respond to immunotherapy. The responses are in the range of 20% to 25% in this context. However, if a patient responds, they have a very high chance to maintain long-term response. In this respect, results from IMvigor 211 and KEYNOTE-045 are quite similar. This is the reason why both agents have been granted approval by the FDA and EMA.

Then, we have other phase II single-agent studies, including nivolumab in CheckMate-275, avelumab, and durvalumab. [These] are very close to the results of pembrolizumab and atezolizumab, with some conflicting signals regarding PD-L1 expression. These compounds are now FDA approved; only one of these other compounds, nivolumab, is granted EMA approval.

It is clear that one of the most important points now is patient selection. At the same time, [we know] that patient selection cannot rely on the role of PD-L1 by immunohistochemistry (IHC) because we don’t have signals supporting the role of predictive PD-L1 expression.

However, we have something else—the results from a translational study, mainly from IMvigor 210 mainly atezolizumab, that are supporting the role of other possible biomarkers. A clear biomarker seems to be the presence of inflamed microenvironment in the tumor, meaning the presence of activating T cells in the microenvironment, which clearly is linked to response and clinical benefit to checkpoint inhibitors.

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