Although immunotherapy seems like a recent phenomenon, physicians have been using the strategy to treat bladder cancer since 1990, when the BCG vaccine, made from a live but weakened tuberculosis bacilli, was approved for early stage cancer that hasn’t invaded the bladder’s muscular wall. Today, BCG is still the recommended standard of care for high-grade noninvasive bladder cancer. In this therapy, BCG in liquid form is place inside the bladder, where it attracts immune cells that attack cancer cells.
More recently, immunotherapy drugs called checkpoint inhibitors have been tested in advanced and metastatic bladder cancer, leading to several drug approvals in the past year for certain patients. As is the case with immunotherapy for other forms of cancer, the drugs help only a minority of patients, but their effectiveness in creating long-lasting benefits for some individuals “has changed the paradigm,” says Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center at Dana-Farber. “I have patients who received immunotherapy who are free of disease two years later,” he adds.
In the most dramatic demonstration of immunotherapy’s potential in this disease, Bellmunt led a phase 3 clinical trial of the checkpoint inhibitor pembrolizumab (Keytruda) in patients whose advanced bladder cancer had recurred or progressed after treatment with platinum-based chemotherapy drugs. The study’s results, reported in the New England Journal of Medicine, showed that patients treated with pembrolizumab had longer survival and a higher response rate than patients who received chemotherapy. In fact, the advantage in favor of the immunotherapy drug was so significant that the trial was stopped earlier than planned. It was the first time an immunotherapy outperformed chemotherapy on a survival basis in this disease, confirming that checkpoint-inhibiting immunotherapy has a role in improving outcomes for bladder cancer – although how large a role remains to be seen.
The response rate for pembrolizumab in this study was 21.1 percent vs. 11.4 percent for chemotherapy, and there was about a 27 percent lower risk of death for individuals who got pembrolizumab. “Side effects are also less frequently seen with the immunotherapy, and quality of life is better,” adds Bellmunt.
These results led the Food and Drug Administration to approve pembrolizumab in May 2016 for patients with locally advanced or metastatic bladder cancer who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
The first checkpoint inhibitor approved for bladder cancer was atezolizumab (Tecentriq), in 2016 for the second-line treatment of patients who had received platinum-based chemotherapy. Response rates were about 15 percent, with a median survival of 7.9 months. Others approved since then include durvalumab (Imfinzi), nivolumab (Opdivo), and, most recently, in May 2017, avelumab (Bavencio).
Despite these approvals and the promising results seen in certain groups of patients, the fact remains that “immunotherapy is only benefiting a small percentage of patients,” Bellmunt says. “There is a lot of room for improvement.”
Researchers are tackling the problem on a number of fronts. One is by trying to identify which patients are going to respond to immunotherapies. Another is to combine immunotherapy agents – with each other, with targeted compounds, or with chemotherapy and radiation. A major caveat with the latter approach is that combinations of immunotherapy drugs often have more prevalent and severe side effects than when the drugs are used alone, so researchers are working to find ways of giving drug combinations while minimizing toxic side effects.