Expert Elaborates on Emerging Advances in Bladder Cancer Care

Petros Grivas, MD

Immunotherapeutic developments in the advanced bladder cancer space have resulted in a number of ongoing combination trials with chemotherapy, targeted therapy, vaccines, and more that could shift the landscape once again.

“It's very interesting to see the ongoing combination trials looking at chemotherapy and immunotherapy together. Beyond these, there are many other potential combination therapies that are worth looking at,” said Petros Grivas MD, PhD, who added there is additional biomarker research being conducted in the field.

OncLive: How has the management of advanced bladder cancer changed?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Petros Grivas, MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discussed ongoing clinical trials exploring novel approaches with the potential to change practice in advanced bladder cancer.Grivas: We are living in a very exciting era with multiple advances in the field of advanced urothelial cancer. Over the last couple of years, we've had significant developments in understanding the molecular biology of advanced urothelial cancer. There have also been developments with immune checkpoint inhibitors. Now, we have 5 approved checkpoint inhibitors for patients with platinum-refractory advanced urothelial cancer. Two of them have been FDA approved for patients with a cisplatin-unfit phenotype.

We have developed data regarding emerging biomarkers in advanced urothelial cancer. A recent press release by the FDA commented on the potential role of PD-L1 immunohistochemistry testing. PD-L1 may be used to try to predict whether patients would respond better or worse to immune checkpoint inhibitors based on PD-L1 expression. This is something we have not done for a long time.

Whether we should look further into that biomarker expression is another debate. For the time being, it is not a companion diagnostic. However, it is something to look for along with the plethora of other putative biomarkers, such as tumor mutational burden, gene expression profiling and subtypes, DNA damage response, and circulating tumor DNA. Many others are being developed and are going to be looked at in prospective clinical trials to evaluate their clinical utility.

In addition to the development of biomarkers, we have therapeutic advances. Clinical trials have evaluated the utility of targeted therapies. We have not been successful with targeted therapies so far. In my opinion, this is a result of improper patient selection. With the advent of more thorough and more accurate next-generation sequencing, we are now able to identify potential targets and/or predictive biomarkers that can help us position these targeted agents in the right clinical trial context.

Right now, we are conducting trials to evaluate whether targeted therapies, such as FGFR inhibitors, may have activity in this disease. Early data from phase I trials in well-selected patients look very promising. Moreover, we have other agents that target the EGFR, HER2, and HER3 family. This is relevant because we can develop potential biomarkers to help us select our patients.

We have data with antibody-drug conjugates. These are toxins that are linked to an antibody that can target a particular protein in urothelial cancer cells. This can lead to the internalization of the toxin, which can potentially kill the cancer cells. Three antibody-drug conjugates have been tested in clinical trials. Two have shown interesting results that are being moved to larger phase II and III trials.

It's important to know that antiangiogenesis agents are being evaluated. There is a pending trial looking at the combination of gemcitabine and cisplatin with or without the anti-VEGF agent bevacizumab (Avastin). The combination will be evaluated in the first-line setting in cisplatin-eligible patients. The trial has been going on for a while but has still not read out yet, which is interesting. There may be less events because people are living longer.

We also had recent results of the RANGE phase III trial looking at ramucirumab (Cyramza) in comparison with docetaxel. The trial met the primary endpoint of progression-free survival benefit. However, the overall survival (OS) data are not mature yet.

Overall, we have plenty of new targets. The other interesting development is our knowledge about DNA damage response (DDR) mutations. DDR alterations could be a target, especially with the development of PARP inhibitors. PARP inhibitors are a very promising compound.

There are trials in urothelial cancer that look very promising that are looking at the potential utility of PARP inhibitors, either in all-comers or patients selected by DDR alterations. These trials are being done alone or in combination with immunotherapy.

Can you elaborate on the use of PARP inhibitors in this setting?

What do we know so far about immunotherapy in advanced urothelial cancer?

There is a plethora of immunotherapy trials ongoing, either single agents or combinations with chemotherapy, other immunotherapies, vaccines, angiogenesis-targeted agents, targeted therapies, and PARP inhibitors. Some people argue that we have more clinical trial slots than actual patients. It's definitely an exciting time. The mechanism of action makes sense, especially in urothelial cancer, because we see DDR alterations in various components of the DDR pathway in different genes. We can also try to measure what we call loss of heterozygosity, which is the target marker of genomic scarring— the damage that is happening in the DNA. That alone can potentially serve as a surrogate marker that could predict response to PARP inhibitors. We don't know for sure, but data in ovarian cancer points in that direction, so it's worth looking at in urothelial cancer, as well.Chemotherapy is still a very important component and tool in our armamentarium, especially for cisplatin-eligible patients. Cisplatin-based chemotherapy is still the standard of care in the first-line setting for advanced urothelial cancer.

However, we are all very excited with the advent of checkpoint inhibitors. Many of those approvals were based on single-arm phase II trials. There have been 2 randomized phase III trials trying to evaluate the role of checkpoint inhibitors with pembrolizumab (Keytruda) versus single-agent taxane in the United States.

The trial met the primary endpoint of a benefit in OS with pembrolizumab as a salvage therapy versus chemotherapy in patients with platinum-refractory advanced urothelial cancer. The median OS difference was about 3 months, favoring pembrolizumab in all-comers.

Based on the assay that was used, patients with higher PD-L1 expression still showed a benefit with pembrolizumab. This led to what we call Level I evidence for the use of pembrolizumab in patients with platinum-refractory advanced urothelial cancer. That agent has the highest level of evidence in the salvage setting in patients who progress on or after platinum-based chemotherapy.

Interestingly enough, the IMvigor211 trial with atezolizumab (Tecentriq) versus chemotherapy did not meet its primary endpoint of OS benefit. The caveat was that the primary endpoint was OS in the subset of patients with high PD-L1 expression. They were only going to look at higher range PD-L1—expressing patients and subsequently all-comers if the primary endpoint was met in the original subset.

It was a hierarchal statistical design, so you had to meet the primary endpoint in high-expressing PD-L1 patients before you moved to all-comers. In my opinion, the problem was that

they used a different assay to evaluate PD-L1 expression compared with other trials. There are many assays, and they are causing confusion in the field.

In the atezolizumab study, the assay showed that patients who had a higher PD-L1 expression lived longer and had better outcomes. In IMvigor211, PD-L1 expression ended up being a positive prognostic biomarker; people did better regardless of treatment. It’s more difficult to discern a difference between the 2 treatment arms if people live longer in this subset. That was probably the main reason why the primary endpoint of the trial read out negative.

If you look at all-comers, there was a significant difference, statistically speaking, with atezolizumab versus chemotherapy in platinum-refractory advanced urothelial cancer. If the study wasn’t designed in a hierarchal fashion, the trial would have been positive, at least by statistical criteria.

Only 1 trial met its primary endpoint of OS benefit in the platinum-refractory setting. The data with atezolizumab and pembrolizumab have equal or comparable level of evidence in chemotherapy-naïve patients in the first-line setting. This is based on the single-arm phase II IMvigor211 study and the KEYNOTE-052 trial. Both of them showed high response rates for that particular population, but still not as high as we want them to be. The response rate was 23% with atezolizumab and 29% with pembrolizumab. However, there were many durable responses, and this durability of response gave significant attention to those agents. That likely played a role in their FDA approval.

The question becomes, “What do you do in patients who have low PD-L1 expression in the first-line setting?” This question is going to be answered in 4 ongoing phase III trials. Two of them are comparing chemotherapy alone, platinum-based therapy or gemcitabine with either cisplatin or carboplatin—depending on cisplatin eligibility—to pembrolizumab or atezolizumab. There are 3 arms in these trials; it’s very interesting.

There are also trials examining the combination of chemotherapy and immunotherapy. There are 2 separate trials looking at the combination of PD-1/PD-L1 or CTLA-4 inhibitors with chemotherapy. These 4 trials are going to map out how we treat patients in the coming years.

Can you speak more on these combination trials with chemotherapy and immunotherapy?

If someone gets first-line gemcitabine/cisplatin or gemcitabine/carboplatin and does not progress, do they enroll in a switch maintenance trial with either immunotherapy or placebo? That is another interesting approach for patients who get first-line gemcitabine, cisplatin, or carboplatin. These maintenance trials are also going to help us with sequencing.Immunotherapy can be combined with chemotherapy and antiangiogenesis agents. There are trials with atezolizumab and bevacizumab in kidney cancer. There is a similar concept being discussed in urothelial cancer. There are data with cabozantinib (Cabometyx) and immunotherapy in kidney cancer. This idea will be evaluated in urothelial cancer.

There are other ideas about combining different checkpoint inhibitors that target different parts of the immune system. We don’t know if this combination with CTLA-4 or other targets will allow for better results with PD-1/PD-L1 inhibitors. The hypothesis is being tested in clinical trials.

Of course, we have vaccines, which are a very promising way to try to prime the immune system for a subsequent checkpoint inhibitor. This is being explored in trials of patients with advanced urothelial cancers.

There is an umbrella trial ongoing with different targeted therapies with genomic sequencing. You pick your target based on genomic sequencing and combine a targeted therapy with immunotherapy to get a synergistic approach. The combination of antibody-drug conjugates with checkpoint inhibition is also an interesting [method]. Moreover, there are some theories about radiation therapy and how it can potentially release neoantigens based on immunogenic cell death.