Balar Discusses Current and Emerging Immunotherapy Treatments in Urothelial Carcinoma

Arjun Balar, MD

Arjun Balar, MD

The successes seen with immunotherapy have been taking the field of urothelial carcinoma by storm, and researchers are still looking forward to the approval of additional immune checkpoint inhibitors in this space.

Currently, the field is fortunate to have 2 checkpoint inhibitors, atezolizumab (Tecentriq) and nivolumab (Opdivo), approved by the FDA, says Arjun Balar, MD, as these agents have proven a survival benefit over the current standard of care.

The potential FDA approval of additional agents, such as durvalumab (MEDI4736), expected later this year, would also be a promising new addition to the armamentarium in urothelial carcinoma, Balar explains. The FDA granted a priority review to durvalumab in December, based on findings from the phase I/II Study 1108, in which durvalumab demonstrated a response rate of 46% in patients with PD-L1—positive advanced bladder cancer.

In an interview withTargeted Oncology, Balar, assistant professor, Department of Medicine, and director, Genitourinary Medical Oncology Program, NYU Langone Medical Center, discussed the treatment considerations he makes when treating patients, the role of PD-L1 tumor expression and immune checkpoint inhibitors, and the potential for new immunotherapy agents in urothelial carcinoma.

TARGETED ONCOLOGY:How do you consider the following factors when deciding on a therapeutic approach for a patient: age, ECOG performance status, renal function, smoking history, and comorbidities?

Balar:

Obviously, the overall medical health of the patient is extremely important to assess likely tolerance of chemotherapy. The most important of these factors are performance status and kidney function because patients who have poor performance status or impaired kidney function consistently do not do well with platinum-based chemotherapy.

A patient’s smoking history and other comorbidities are also important factors. Smoking cessation is extremely important, and managing other comorbidities to make sure they are well controlled is also very important. Age alone is not a consideration when treating a patient; however, advanced age comes along with other medical problems.

TARGETED ONCOLOGY:What is the role of PD-L1 tumor expression in the case of a patient with advanced bladder cancer?

Balar:

PD-L1 tumor expression in this setting, given the current standards of care, have a limited role. Immune checkpoint inhibitors have demonstrated a survival benefit in the second-line setting and against an active comparator, which is chemotherapy. That is the only evidence that we currently have for any treatment in the second-line setting. Therefore, PD-L1 expression has a very limited role in this particular setting because even patients who are low PD-L1 expressers have been shown to respond.

For a patient like this, similar to the other 2 cases, PD-L1 testing has a limited role. In the current era, where we have single-agent immunotherapy as approved agents and it is essentially the defacto second-line agent of choice, patients who are PD-L1—negative may also potentially benefit. The real challenge is deciding ultimately if a patient is a candidate for an immune checkpoint inhibitor.

TARGETED ONCOLOGY:What treatment would you suggest for a patient with severe comorbidities? Are they a candidate for immune checkpoint inhibitors?

Balar:

These patients were excluded from clinical trials for checkpoint inhibitors and so these patients are not technically candidates for an immune checkpoint inhibitor. The challenge in the real world is that patients who are facing a life-threatening illness, such as advanced cancer, may decide to take the risk of receiving an immune checkpoint inhibitor at the potential cost of worsening their autoimmune syndrome. If this is something that is elected to be done, as a shared decision between the oncologist and the patient, I would strongly encourage that a rheumatologist be closely involved in managing this patient so that should their autoimmune disorder flare in the context of immunotherapy be quickly and aggressively controlled with additional agents as needed.

TARGETED ONCOLOGY:Will all patients with bladder cancer receive immunotherapy either upfront or at progression?

Balar:

My belief is that in metastatic urothelial cancer, immunotherapy will be a standard of care at some point in the patient’s course of therapy, whether it be frontline or second line, unless there are clear contrary indications for the patient to receive it, so I believe the scope of this therapy will be very broad and essentially applied to almost all patients with advanced bladder cancer at some point in their disease.

TARGETED ONCOLOGY:With so many to choose from, how do you choose which checkpoint inhibitor is the right choice?

Balar:

At this point, I think the field and patients are quite fortunate to have different choices between atezolizumab (Tecentriq) and nivolumab (Opdivo), which are both approved. We are expecting additional approvals to occur within the next year. At this point, it’s very difficult to discriminate between these agents. The most we can say is that they both have comparable efficacy, as well as safety profiles, and it appears that PD-L1 testing does associate with response probability. At this point, I think it’s too difficult to choose between agents, and they appear to be fairly comparable.

TARGETED ONCOLOGY:What is important to know about toxicity management with immunotherapy in bladder cancer?

Balar:

The most important things to know about toxicity management in immunotherapy in general, not just in bladder cancer, is the importance of early diagnosis and management of immunotherapy-related toxicities, in particular diarrhea and immune-related colitis, as well as pneumonitis, as these do occur in patients receiving immunotherapy. Rapid diagnosis and management is key to prevent life-threatening consequences.

TARGETED ONCOLOGY:What are some treatments on the horizon in bladder cancer? How would the approval of durvalumab impact treatment?

Balar:

There are several new treatments currently in development in bladder cancer. These include additional PD-L1 targeted agents, such as avelumab and durvalumab. Also, other immune checkpoint inhibitors such as anti—CTLA-4 antibodies ipilimumab (Yervoy) and tremelimumab are in development in combination with PD-1/PD-L1 antibodies and may lead to higher rates of response, but are also associated with higher rates of immune toxicity.  

Also, a novel antibody-drug conjugate ASG-22CE, which targets nectin-4, is also a promising new agent in phase I trials, and will be entering phase II studies soon.

The potential approval of durvalumab in second-line bladder cancer would be a promising new addition to the armamentarium in bladder cancer.