Next Steps in Bladder Cancer to Include Combination Immunotherapy

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

The other point has to do with…the population of patients who harbor luminal tumors. Patients who are usually less likely to respond to immunotherapy [may harbor] FGFR alterations. FGFR is another target of another class of agents, pan-FGFR receptors, that are coming into the ground of bladder cancer treatment. The results of these trials would be presented in the first quarter of [2018]. The biology behind the possible association between FGFR alteration and poor response to PD-1/PD-L1 inhibitors strongly supports the possible use of this class of agents prior to or following the use of immune checkpoint inhibitors. We are now almost able to shape patients’ journeys, which seems to be worldwide, in order to identify possible druggable targets to be used prior to immunotherapy, or following progression on immunotherapy.

There is still a role for old chemotherapy. There is still undoubtedly a role for cisplatin-based chemotherapy. Then, there is a possible role for chemotherapy after disease progression on checkpoint inhibitors. We have seen augmented activity of chemotherapy after prior exposure to checkpoint inhibitors; they are very small numbers but it seems chemotherapy may still have a role after the use of checkpoint inhibitors.

What has been the impact of PD-1 inhibition in bladder cancer?

The impact may be perceived and may be discussed on multiple perspectives. I would say, first, the most important impact has to do with the patient perspectives. For the first time, in this disease, we can hear the voice of patient advocates in bladder cancer—in Europe mainly.

Since then, we have achieved important steps forward together with patients in Europe and we are trying to create a community of patients in Europe. The next step would be to try to better use these options in additional medical needs; for example, the issue of bladder preservation to not only cure advanced disease, but to preserve the disease in early stages. The use of immune checkpoint inhibitors may be regarded as a hope for patients, in order to have a better understanding of the way we can spare their bladder.

Does having a phase III improvement in OS sway doctors toward treatment with pembrolizumab?

Yes, not only from a regulatory viewpoint, but from the investigator and clinician viewpoint. We are handling data that may come from multiple trials, but most of the data are coming clearly from pembrolizumab. At the same time, there were results achieved with nivolumab, atezolizumab, avelumab, and durvalumab that are quite close to those of pembrolizumab. But, conservatively, we should first look at pembrolizumab data and then all the other phase II data are coming down.

What is the importance of PD-L1 testing?

There are no roles so far for PD-L1 testing. All of the drugs being granted registration by the FDA and EMA are not being granted based on the use of PD-L1 via IHC; they are for all comers, regardless of PD-L1 expression.

At the same time, the process of patient selection and the need for selecting patients is a priority because we cannot afford the contemporary use of 5 different very similar compounds in all comers. Therefore, investigators are clearly asked to [do their] best to identify criteria for patient selection.

Of course, one of the most important notions that we have coming and moving beyond the role of PD-L1 expression comes from the mutational burden, which seems to be linked to the activity of immune checkpoint inhibitors. Mismatch repair deficiency is also clearly linked to the activity of immune checkpoint inhibitors. The class of patients less likely to respond to checkpoint inhibitors should be the next targets for clinical evaluation. The point will be to try to translate all these notions into something that may be used effectively and in clinical practice. However, the issue of patient selection is a priority based on the availability of so many similar compounds.

I am very eager to start our phase II study. The phase II study, which will run first in Milan, [Italy], the PEANUT study, is combining pembrolizumab with nab-paclitaxel (Abraxane). Nab-paclitaxel has already shown in the second-line setting to be an active compound in bladder cancer. There is a randomized study that is comparing nab-paclitaxel with a taxane in Canada. Nab-paclitaxel is one of the most effective [chemotherapy agents] in the platinum-treated population. There is an issue with tolerability; of course, one of the endpoints will be to try to prolong PFS.

We know that with the use of pembrolizumab alone, as well as the other immune checkpoint inhibitors alone, we cannot improve PFS. This is another very interesting point regarding the primary endpoints of these studies.

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