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Urothelial Carcinoma Experts Optimistic for Durvalumab/Tremelimumab Combo

Danielle Bucco
Published Online:9:00 PM, Tue May 23, 2017

Peter Black, MD

The recent explosion of FDA approvals in the field of urothelial carcinoma, first and foremost, offers patients options for subsequent lines of therapy, says Peter Black, MD. However, it also raises the question of which of these 5 immunotherapy agents physicians should use.
 
In an interview with Targeted Oncology, Black, senior research scientist, Vancouver Prostate Center, associate professor, Department of Urologic Sciences, University of British Columbia, discussed how 1 of these options, durvalumab (Imfinzi), will fit in the treatment paradigm of urothelial carcinoma, as well as ongoing research in the field.
 
TARGETED ONCOLOGY:  Can you discuss ongoing combination trials with durvalumab?
 
Black: We know that durvalumab works as a monotherapy in the second-line setting after cisplatin failure and I think 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. 
 
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, they are often smokers, and have other medical problems, raising the question of if combinations will be tolerated well.

TARGETED ONCOLOGY: How will durvalumab be sequenced through multiple lines of therapy?
 
Black: 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).
 
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.
 
TARGETED ONCOLOGY: With all of the recent FDA approvals, how do you choose which immunotherapy to give to patients?
 
Black: Right now, we don't know. I think a lot of medical oncologists will have their favorite. For example, if they are treating other cancers sites and 1 of the drugs is approved for the other cancer, maybe that will be their go-to drug. We just heard that a phase III trial of atezolizumab 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. 
 
TARGETED ONCOLOGY: What impact have these new FDA approvals had on the field of bladder cancer?
 
Black: 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.
 
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.
 
TARGETED ONCOLOGY:  In your opinion, why has bladder cancer research seemed to fall behind?
 
Black: 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.
 
TARGETED ONCOLOGY: Are there any potential agents in the pipeline that look promising?
 
Black: 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.
 
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. 
  
TARGETED ONCOLOGY: Can you discuss where we currently are with biomarker research for bladder cancer?
 
Black: Only about 20% to 25% of patients have an objective response. 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. 

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