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There are two immunotherapy options approved for first-line treatment of metastatic urothelial cancer in patients who are platinum-ineligible. In 2017, the FDA granted accelerated approvals to (Tecentriq) and (Keytruda) for patients with advanced disease who are unable to receive cisplatin chemotherapy -- the recommended first-line option.

"Currently, the role of immunotherapy is waning a bit in the frontline space," said Shilpa Gupta, MD, director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at the Cleveland Clinic in Ohio.

Initially, pembrolizumab was approved for metastatic disease that was not eligible for cisplatin-containing chemotherapy. However, the labels to patients who were ineligible for cisplatin-containing regimens and had tumors that are PD-L1 high, or patients who were not eligible for any platinum-containing therapy regardless of PD-L1 status, after data from two clinical trials showed worse outcomes with pembrolizumab or atezolizumab compared with platinum-based chemotherapy in patients with low or no PD-L1 expression. the use of FDA-approved companion diagnostic tests to determine PD-L1 levels.

More recently, to pembrolizumab in metastatic urothelial carcinoma, further narrowing the label to include only patients ineligible for platinum-containing chemotherapy.

"For atezolizumab, the old label is still in place, but the data are under review by the FDA," Gupta told 番茄社区app.

Ineligibility

The average age of patients diagnosed with bladder cancer is 73, show.

"In this older population, there are going to be a number of contraindications to using cisplatin-based chemotherapy," said Gary D. Steinberg, MD, of NYU Langone Health in New York City. "The most common contraindication is renal dysfunction, but neurotoxicity, hearing loss, frailty, and significant cardiac issues are also concerns in this older population."

Given these concerns, there may be as many as 50% of patients with metastatic urothelial carcinoma who have contraindications to cisplatin-based chemotherapy, Steinberg told 番茄社区app.

He explained that being classified as completely platinum-ineligible would also require ineligibility to receive carboplatin-containing regimens. In the immunotherapy approvals, exact criteria for platinum-ineligibility was left up to the provider.

With the label narrowing to patients who are considered truly platinum ineligible, Gupta explained that she and her colleagues have attempted to better define this patient population.

Gupta and other members of the Bladder Cancer Working Group presented from two rounds of a survey of 56 genitourinary medical oncologists in the United States with the goal of finding a clear definition of "platinum-ineligible."

She said that based on the responses, the group determined that platinum-ineligibility could be defined by any one of the following five parameters:

• ECOG performance status 3 or higher

• Creatinine clearance <30 ml/min

• Peripheral neuropathy >3 or higher

• New York Heart Association Heart Failure Class >3 or higher

• ECOG performance status 2 and creatinine clearance <30 ml/min

Gupta said that based on these criteria, only a minority of patients would be included in the definition -- perhaps around 10%.

In addition to eligibility, clinicians must also consider suitability for immunotherapy. This includes a review of comorbid conditions, use of immunosuppressants or high-dose steroids, and presence of serious autoimmune disease.

Better Options

If a patient is identified as a good candidate for first-line immunotherapy, there are no data to guide physicians on choosing between the two available options, Steinberg said.

"As a class all checkpoint inhibitors have about 10% to 12% rates of immune-related adverse events," Steinberg said. "My own personal feeling is that a PD-1 inhibitor is more effective because it blocks interactions with PD-L1 and PD-L2, and I'm not sure a PD-L1 inhibitor is as effective. But data are limited and no head-to-head trials have been performed."

He said that with pembrolizumab's increasing use in all aspects of urothelial cancer treatment, he believes that clinicians will become more familiar with the agent, and more likely to use it. However, neither atezolizumab nor pembrolizumab monotherapy is ideal, he cautioned.

"In bladder cancer, regardless of the checkpoint inhibitor, you will see about 20% durable response rate, which is clearly not good enough," Steinberg continued. "That is a solid response for a single agent, but we are trying to at least double that and have synergistic efficacy."

There is ongoing research into immunotherapy doublets or other combination therapies in the first-line metastatic setting, he added.

"In these cases, by giving an additive therapy we are trying to double responses. The holy grail, though, would be finding a regimen with synergistic benefit to get responses around 60% or so," he said.

Immunotherapy may soon have more competition in the first-line treatment of patients with platinum-ineligible disease. For example, in December 2019 the antibody drug conjugate enfortumab-vedotin (Padcev) was granted accelerated for people with advanced bladder cancer that progressed despite treatment with two previous therapies.

More , the drug was given full approval and the label was updated to include patients who are ineligible for cisplatin-containing chemotherapy and previously had one or more prior lines of therapy.

Steinberg said this label update reflects the general trend of many new therapies moving further and further up in the treatment of diseases. He noted that he is currently involved in a trial testing an intravesical formulation of enfortumab-vedotin for people with Bacillus Calmette-Guérin-resistant non-muscle-invasive bladder cancer.

Sacituzumab govitecan, another antibody drug conjugate, has also recently been FDA approved for metastatic urothelial cell carcinoma. In addition, erdafitinib, a fibroblast growth factor (FGFR3) inhibitor, is FDA approved as second-line therapy for metastatic urothelial cell carcinoma with FGFR3 alterations or mutations. Additional combinations include checkpoint inhibitors plus chemotherapy and in combination with tyrosine kinase inhibitors.

"Last but not least I am also interested in developing personalized cancer vaccines that will help to prime the tumor microenvironment and drive T cell traffic," Steinberg said. "The hope is that this can be given with a checkpoint inhibitor to enhance response."

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