Expert Shares Potential of Durvalumab in Patients With Urothelial Bladder Cancer

Saeed Rafii, MD, PhD, MRCP

Phase I/II findings of durvalumab presented at the 2016 ASCO Annual Meeting show that the PD-1 inhibitor elicited a 46% objective response rate (ORR) in patients with high PD-L1—expressing advanced urothelial bladder cancer.¹

In the study, durvalumab was administered at 10 mg/kg in 61 patients every 2 weeks for up to 12 months. Across all evaluable patients enrolled in the study, the ORR was 31% (95% CI, 18-47). When considering those with stable disease, the disease-control rate (DCR) was 48% across the full population. In patients with high PD-L1 expression (≥25% staining of cells), the DCR was 57%.

The most common adverse events (AEs) with durvalumab, all of which were grade 1 or 2, were fatigue (13%), diarrhea (10%), decreased appetite (8%), arthralgia (7%), asthenia (7%), nausea (7%), and pyrexia (7%). Three patients had grade 3 AEs, which included acute kidney injury, infusion-related reaction, and tumor flare.

Earlier this year, durvalumab received a breakthrough therapy designation from the FDA as a potential treatment for patients with PD-L1—positive inoperable or metastatic urothelial bladder cancer. Additionally, durvalumab is currently being explored in clinical trials in more than 7000 patients with 19 different types of cancer.

OncLive: Can you give an overview of your abstract regarding durvalumab in urothelial bladder cancer?

What are the most significant findings from this study?

What do you think are going to be some of the next steps following this study?

Can you tell us about the mechanism of action of durvalumab?

To gain more information into the potential role for durvalumab in urothelial bladder cancer, OncLive spoke with Saeed Rafii, MD, PhD, MRCP, one of the investigators of the phase I/II study. Rafii, Medical Director and Consultant Medical Oncologist, Sarah Cannon Research Institute UK, discussed the PD-L1 inhibitor, as well as what the future could hold for the treatment of patients with bladder cancer.Rafii: I recently presented Study 1108 in urothelial bladder cancer. Study 1108 was a large, phase I dose-escalation, dose-expansion clinical trial of durvalumab in different solid tumor cancers. More than about 1000 patients with 15 different tumor types participated in this clinical trial, and we recently presented data on about 61 patients in urothelial bladder cancer.The most significant findings from the study was the impressive ORR to durvalumab in urothelial bladder cancer, which is a really significant response rate considering response rates to chemotherapy is quite low. Over the past 20 years, there really hasn't been an advance in the treatment of patients with bladder cancer.The next steps following this study would be first of all to find out whether durvalumab—or in fact any anti-PD-L1— can perform better than chemotherapy. Of course, we need to find out the biomarkers for the response to this treatment. We also need to find out if there's going to be an improvement in overall survival rates in combination with other agents, such as with anti—CTLA-4 inhibitors or other targeted agents.Anti—PD-L1 inhibitors, of course, they inhibit anti–PD-L1 and they enable the T lymphocytes to infiltrate the tumor and kill the cancer cells. They are not a cytotoxic agent on their own and they enable the immune system to be able to fight with the cancer.

The mode of action is the same, but they are different agents from different companies. I think to begin with, we have a lot of other questions to answer first. We need to find out whether or not there are biomarkers of response to the treatment other than PD-L1 expression. That is one, and secondly we need to find out whether or not this agent combined with other agents can be compared with chemotherapy.

Can you discuss the major challenges in treating bladder cancer?

There was a question recently regarding patients who have had bacillus Calmette-Guérin (BCG): will they do better or worse? There are a lot of questions unanswered to begin with. At some point there may be that comparison, but I don't think it will be any time soon.For over 20 years, there hasn't been any advance in treatment of bladder cancer. We have challenges in bladder cancer in terms of the kidney function, and we know that's from some of the agents we give. The rate of toxicities relating to these agents, they are not really high.

Where do you envision the treatment landscape going in the next few years?

In durvalumab, for instance, only 1 patient had a grade 3 drug-related acute kidney injury, which was reversible. In terms of treatment-related adverse events, I think generally speaking the treatments we have are very well tolerated. It is just a patient selection to make sure that we select patients who are not unwell enough to develop toxicities from these treatments.Certainly, we will have more trials with anti—PD-L1 in bladder cancer. We are going to have a combination of anti–PD-L1 and anti–CTLA-4 treatments; there are a couple of basket studies at the moment trying to look at different combinations with, for instance, olaparib (Lynparza) in bladder cancer.

There is a new trial that's currently looking at durvalumab in comparison with chemotherapy. In the next few years, we will hear more about anti—PD-L1 treatments, whether that's head-to-head with chemotherapy, as a single agent, or in combination with different agents.

Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), a PD-L1 antibody, in urothelial bladder cancer. J Clin Oncol. 2016;34 (suppl; abstr 4502).