Bladder Cancer: Immunotherapies, Combination Therapies, and Current Research

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Several promising drugs have been approved for the treatment of bladder cancer within the phase year, but combination therapies may be still more effective.
Several promising drugs have been approved for the treatment of bladder cancer within the phase year, but combination therapies may be still more effective.

Editor's note: this article was updated after the recent approval of durvalumab on May 1.

Breakthroughs in the treatment of bladder cancer are ongoing.

After years with few therapies for combating the disease, 3 new immunotherapies were approved by the US Food and Drug Administration (FDA) in the last year. Yet another is under priority review for similar frontline application, with approval anticipated shortly.

“This class of therapies is quickly reshaping both our treatment approach for this cancer as well how we approach understanding the disease from a biological standpoint,” said Arjun Vasant Balar, MD, assistant professor of medicine at the New York University (NYU) Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center in New York.

The impact, he continued, “is quite profound, because the therapy itself is changing how future treatments might be designed.”

Bladder cancer is the sixth most common type of cancer, and the ninth leading cause of cancer death. It accounts for nearly 5% of all new cancer cases in the United States. The National Cancer Institute estimates that 79,030 new cases will be diagnosed in 2017. Of those, an estimated 16,870 patients will die.1

The standard of treatment in early stage, non–muscle invasive bladder cancer relied on Mycobacterium bovis bacillus Calmette-Guérin (BCG). Initially discovered in the treatment of tuberculosis, intravesical BCG proved to be, as a 2012 study described it, “superior to any other single chemotherapeutic agent for reducing recurrence and preventing progression. Typical complete response rates are 55-65% for papillary tumors and 70-75% for carcinoma in situ.”2

However, the study continued, “30-45% of patients will be BCG failures. Of the complete responders, up to 50% will have a recurrence. Furthermore, side effects range from cystitis and irritative voiding symptoms to much more uncommon life-threatening BCG sepsis. Up to 20% of patients are BCG intolerant due to these side effects.”

But BCG is useful only for non–muscle invasive disease. Once the cancer invades muscle tissue or metastasizes, the standard of care — which has been used since the 1980s — involves combinations of chemotherapy agents, including cisplatin. Combination chemotherapy regimens yield objective response rates of more than 50%, with a median survival of 12 to 15 months.

The Immunotherapy Revolution

In 2016, the FDA approved the first PD-1/PD-L1 inhibitor for the treatment of metastatic chemotherapy-refractory bladder cancer.3

At the time, the agency specifically limited its approval of atezolizumab as a second-line treatment for “patients with locally advanced or metastatic urothelial carcinoma whose disease has worsened during or following platinum-containing chemotherapy, or within 12 months of receiving platinum-containing chemotherapy.”

In February 2017, the administration granted similar approval to nivolumab as a second-line treatment for patients who do not respond to chemotherapy.4

In studies leading to their approval, both immunotherapies resulted in objective response rates of 15% to 20%. Even more remarkable, Dr Balar noted, are their durability.

RELATED: FDA Grants Atezolizumab Accelerated Approval for Bladder Cancer

“That number itself is not eye-popping and does not draw a lot of attention until you look at how durable the responses are,” he said. “It looks to be at least two-thirds of these responses are durable with intermediate to long-term follow-up so far.”

This may explain the seemingly-continuous string of FDA approvals of immunotherapies for this setting. On April 17, it announced the approval of atezolizumab as a frontline therapy for metastatic bladder cancer based on a nonrandomized phase 2 trial Dr Balar led.5

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