Future of Bladder Cancer Care to Include Immunotherapy Combos

Petros Grivas, MD

Immunotherapy is likely to represent the future of bladder cancer care, especially in combinations with chemotherapy and targeted therapy regimens, according to Petros Grivas, MD.

“Recently, we had the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) in patients with kidney cancer, said Grivas, a medical oncologist at the Cleveland Clinic. “The question is how this combination will go through in patients with urothelial carcinoma.”

An ongoing phase I study examining cabozantinib (Cabometyx) plus nivolumab with or without ipilimumab is currently accruing patients (NCT02496208). This study aims to the determine the safety and tolerability of a novel dose of cabozantinib, nivolumab, and ipilimumab in patients with urothelial cancer and other GU malignancies.

OncLive: Please provide an overview of your presentation on bladder cancer.

In an interview during the 2017 OncLive^® State of the Science on Genitourinary Cancers^TM, Grivas shared insight on the value of combining immunotherapy regimens in the treatment of patients with urothelial carcinoma.Grivas: I discussed the recent updates with immunotherapy, specifically immune checkpoint inhibitors, in the management of patients with advanced urothelial carcinoma. Over the last couple of years, we have seen data with 5 FDA approvals of immune checkpoint inhibitors for the management of patients with platinum-refractory advanced urothelial cancer.

Two of them have been approved in the first-line setting and they present new treatment options for those patients. I reviewed the data behind these approvals of these 5 agents. We sorted through safety, efficacy, and the level of evidence for each of those agents.

In addition, we gave a snapshot of what the treatment options are for patients with advanced urothelial cancer. We have new chemotherapy, immunotherapy, and clinical trials that consider the treatment of this current landscape. We captured some promising combination therapies as examples of what is happening in the clinical trial setting and which combinations might look promising enough to move onto phase III clinical trials.

We have those 5 checkpoint inhibitors now available. What is next for the treatment landscape?

Moreover, we are discussed some concepts of biomarkers and how these might be used in the future. We touched upon the prospect of different promising scenarios in the future in terms of looking at patient selection based on those biomarkers.This is a great environment since there are many ongoing clinical trials…We are approaching a thousand clinical trials across tumor types evaluating different combinations of immunotherapy—either with other immunotherapy agents or chemotherapy or targeted therapy. We have a plethora of information in clinical trial designs that we are sorting through. Some interesting combinations might come through but, recently, we had the combination of ipilimumab and nivolumab explored in patients with kidney cancer. The question is how this combination will fare in patients with urothelial carcinoma.

We have 4 large clinical trials looking at combination immunotherapy or single-agent immunotherapy versus chemotherapy in the first-line setting of patients with advanced urothelial cancer. Two of those trials are testing the combinations of chemotherapy plus immune checkpoint inhibition. Moreover, we have maintenance trials in which patients after first-line chemotherapy are randomized to either immunotherapy with checkpoint inhibitors or observation or placebo depending on the trial to evaluate the concept of the maintenance approach before progression to prolong progression-free survival and overall survival.

Can you explain the synergy that exists with immunotherapy and chemotherapy and why that might be an exciting combination for the field?

There are multiple combinations looking at different immunotherapy compounds that target different components of the immune system. PD-1 with IDO or any other compounds are critical players of the immune system. An approach that I find interesting is the combination of targeted therapies with immunotherapy. It might have a significant role in selected patients based on the presence of genomic alterations that define patient subsets who will benefit from targeted therapy approaches.Chemotherapy by itself may have the opportunity and potential to induce changes in the tumor microenvironment. We have some data from the Cleveland Clinic where we looked at tissue expression of PD-L1, PD-L2, and PD-1 with the gene expression profiling before and after neoadjuvant chemotherapy. It was mainly with cisplatin, which is the standard of care in that setting.

We did see the expression of PD-L1/PD-L2 after neoadjuvant chemotherapy in different patients. Some patients had lower expression of PD-L1/PD-L2 at the cystectomy specimen compared with the transurethral resection of bladder tumor specimens. Other patients have either stable expression or increased expression of PD-L1/PD-L2. The latter category of patients who had increased or stable expression of PD-L1 had worse outcomes and earlier recurrence. The hypothesis is if you combine chemotherapy with immunotherapy, you may have synergistic results.

What are some targeted agents that can be combined with immunotherapy?

There is also the theoretical concept of immunogenic cell death in which base cancer cells might die and the result of this dying process may release new antigens that can be picked up and recognized by the immune system. This can perpetuate, for some, a new response. These are theoretical concepts, so we will have to evaluate whether this materializes in clinical practice. There is a plethora of targeted therapies being evaluated in clinical trials. Thus far, we have not been successful in having targeted therapies for the treatment of patients with urothelial cancer. There have been multiple reasons for that but the most important was the lack of patient selection. We did not have good biomarkers to select our patients for targeted therapies in urothelial cancer. Currently, with the advances in genomic sequencing, patients who identify mutations, amplifications, or fusion rearrangements of genes may be more predictive of a response to targeted agents compared with immunohistochemistry or other conventional previously used approaches.

We are becoming better at selecting our patients. Potential targets include FGFR3, which is being targeted by either antibodies or tyrosine kinase inhibitors. There is a lot of interesting promising data in phase I and phase II trials with these targets in urothelial cancer.

There is also some important and promising data in a phase II trial in patients with HER2, HER3, and possibly EGFR genomic alterations with an agent that inhibits an EGFR, HER2, and HER4 receptor. This phase II trial presented results in the Journal of Clinical Oncology, which led to the design of the phase III trial looking at pan-HER receptor inhibition in patients with genomic alterations in this family.

How will the role of PD-L1 will evolve as a biomarker?

Moreover, there is high interest and data in antiangiogenesis agents that are being evaluated in urothelial cancer. There are trials that are being conducted that evaluate combinations of those targeted compounds with immunotherapy. We need to wait to see whether these trials pan out or not. PD-L1 has been a continuous dynamic story that keeps evolving. The short answer is that we do not use the PD-L1 protein immunohistochemistry expression as a clinically useful biomarker in urothelial cancer. To the best of my knowledge, this is the case for all other cancers in which checkpoint inhibitors are being used. The exception is in first-line non—small cell lung cancer where there is utilization of PD-L1 staining but besides that all other tumor types do not utilize PD-L1 expression as a predicative biomarker.

In my opinion, we have to move beyond PD-L1 as a predictive biomarker because it is not a perfect biomarker. It can select some patients, but we still see responses in urothelial cancer either in patients with or without PD-L1 expression and even patients without high PD-L1 expression may have response rates comparable with the historical rates of chemotherapy. Therefore, PD-L1 alone has not been a clinically useful biomarker in urothelial cancer.

I am interested in looking at multiple different biomarkers through research. Mutational load appears to be the most promising in terms of the values and correlations with responses. This is not only for urothelial cancer, but for other cancers, too. The theory behind mutational load is the synthesis of novel antigens that can be recognized by the immune system through this mutation process.

Now that we have these immunotherapy options, what role with Bacillus Calmette-Guérin (BCG) have in the future?

Moreover, there are data about an expression profiling that tells us that different molecular subtypes of urothelial cancer may have differential response rates to immunotherapy. We have to evaluate composite biomarkers and integrate the data with novel platforms and evaluate the clinical utility of the biomarker before clinical use. BCG does have an important role in the treatment of non-muscle invasive bladder cancer (NMIBC), especially in the beginning when someone is first diagnosed with high-grade NMIBC. BCG has an established role since it has high response rates. That is why we do not see many trials in the BCG-naïve setting. We see many clinical trials, including checkpoint inhibitors, in the BCG relapse setting with anti—PD-1/PD-L1 agents. This is to evaluate their role for patients who already had BCG and either progress or had recurrence of their disease.

It is important to keep in mind that rational combinations can be evaluated in the non-muscle invasive disease space. There are thoughts about designing clinical trials of BCG combined with other immunotherapy agents, especially in the BCG relapsing and unresponsive NMIBC space. For now, BCG does continue to have an established role, especially in patients with BCG-naïve non-muscle invasive high-grade disease.