Expert Discusses Next Steps for Durvalumab in Bladder Cancer

Peter Black, MD

Durvalumab (Imfinzi) was approved by the FDA in May 2017 for patients with locally advanced or metastatic urothelial carcinoma who received platinum-containing chemotherapy and have disease progression.

Researchers are now aiming to both optimize durvalumab monotherapy and explore the PD-L1 inhibitor in combination regimens. For example, durvalumab is being evaluated as a single agent and in combination with tremelimumab in the phase III DANUBE trial in the frontline setting for patients with metastatic urothelial carcinoma (NCT02516241).

OncLive: Can you discuss ongoing combination trials with durvalumab?

In an interview with OncLive, Peter Black, MD, a senior research scientist, Vancouver Prostate Centre, associate professor, Department of Urologic Sciences, University of British Columbia, discusses the latest on durvalumab and other ongoing developments in the field of bladder cancer.Black: We know that durvalumab works as a monotherapy in the second-line setting after cisplatin failure. The first trial that we completed in the first-line for cisplatin is a combination trial of durvalumab versus durvalumab plus tremelimumab versus standard chemotherapy. Everyone is excited and anxious to see the results of that trial.

How will durvalumab be sequenced?

We know from other disease sites that the combination works well, making people optimistic. Combinations in general, such as a CTLA-4 inhibitor plus a PD-1/PD-L1 inhibitor, will face the question of toxicities. Bladder cancer patients are generally older, are often smokers, and have other medical problems, raising the question of whether combinations will be well tolerated.We’re lucky in bladder cancer that we can now talk about sequencing, since this was never an issue before. A patient with metastatic disease would get a traditional cisplatin-based chemotherapy first if they could tolerate it and then receive a drug like durvalumab or another checkpoint inhibitor. If they’re cisplatin-ineligible, then an alternative drug that’s approved in that setting is atezolizumab (Tecentriq).

Given the multiple FDA approvals, how do you choose which immunotherapy to give to patients?

What impact have these FDA approvals had on the field of bladder cancer?

When we have another drug approved in the first line, then we’re going to have to figure out which one should be given first. Presumably, we would give the checkpoint inhibitor first because the toxicity will be lower and there will be some durable response. Only 20% or so will respond, so the others will have to move on to chemotherapy, but it remains to be determined. Right now, we don't know. I think a lot of medical oncologists will have their favorite. For example, if they are treating other cancer sites and 1 of the drugs is approved for the other cancer, maybe that will be their go-to drug. We heard that a phase III trial of atezolizumab (IMvigor211) was negative. That trial is first out of the gate which is an advantage, but now they have negative trial data to deal with. We just have to see where the dust settles with all of these changes. Every other day there is something new. First and foremost, it is giving patients another option. It’s given them hope that they have another round of therapy. Some of them respond very well, which is the most important thing.

In your opinion, why has bladder cancer research seemed to fall behind?

Are there any potential agents in the pipeline that look promising?

It’s also brought a lot of interest to bladder cancer—both industry interest and research interest—which just furthers the field more in terms of drug and biomarker development. Bladder cancer clinical and translation research has lagged behind many other cancers. The whole targeted therapy era has bypassed bladder cancer so this has infused some necessary energy and dollars into bladder cancer research. Part of it might be a lack of advocacy. Now, in the United States, we have a Bladder Cancer Advocacy Network, which is a great organization that is promoting the cause. Since the industry has not been interested in bladder cancer, they have not wanted to fund trials. This makes our molecular understanding fall behind, and without understanding some of the biology, it’s hard to pick the right treatment and design the right trial. There are other checkpoints that are being targeted, so hopefully we’ll have new checkpoint inhibitors and immunotherapies. But, all the work is not done on just immunotherapy. There are other treatments as well.

Can you discuss where we currently are with biomarker research for bladder cancer?

The clinical trial field has become very complex as things move upstream. There are adjuvant trials after radical cystectomy and before radical cystectomy, and trials in non-muscle invasive bladder cancer. The whole spectrum is being covered, so there is a lot happening. Only about 20% to 25% of patients have an objective response [to immune checkpoint inhibitors]. The drugs are expensive and potentially toxic so we want to rationalize who should get them and who shouldn’t. Back in the beginning, there was always biomarker development with these drugs and the easy one is PD-L1 immunohistochemistry, which hasn’t quite panned out and it currently has no utility in bladder cancer patients.

There is molecular subtyping based on RNA subtypes, which is interesting, but we don’t know enough. What we know is from 2 different trials and they both show quite different results, so that is under further investigation. Additionally, the rate of mutations in the tumor has a reflection of neoadjuvant load and we think that more antigens cause higher immunogenicity that will make tumors more sensitive to immune therapy, which is a promising tool.

There are newer ones coming along, such as peripheral immune cells and sequencing T-cell receptors. There is almost as much going on in the biomarker field as there is in the direct treatment development.