Treatments that improve the immune system’s ability to recognize and kill cancer cells are known as immunotherapy. For certain patients with advanced bladder cancer, immunotherapy is proving effective, and several immunotherapy drugs are approved for use in such patients.
Currently approved treatments
A checkpoint inhibitor is a drug — often made of antibodies — that unleashes an immune system attack on cancer cells. The U.S. Food and Drug Administration (FDA) has approved five immune checkpoint inhibitor drugs for patients whose advanced or metastatic bladder cancer has progressed following treatment with platinum chemotherapy:
Pembrolizumab and atezolizumab are also approved as first-line treatment for some patients with advanced bladder cancer who can’t tolerate cisplatin chemotherapy and also have high expression of the PD-L1 protein on the tumor and/or immune cells. High levels of the PD-L1 protein provide targets for checkpoint inhibitor drugs to act on, releasing brakes that have kept the immune system from attack the cancer.
Additionally, pembrolizumab and atezolizumab were approved as first-line treatment regardless of PD-L1 expression for those who cannot tolerate any platinum chemotherapy, such as cisplatin or carboplatin, because of poor general health or kidney function or other illnesses.
Although these immunotherapy agents are, as of now, effective in inducing response only in 15 or 20 percent of patients treated with them, “most of the responses are very durable,” says Guru Sonpavde, MD, bladder cancer director in the Lank Center for Genitourinary Oncology at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC).
“Pembrolizumab has demonstrated improved survival with the duration of response exceeding a median of two years in a phase 3 trial in patients whose cancer had progressed following platinum chemotherapy,” Sonpavde adds.
Following completion of first-line platinum-based chemotherapy, metastatic bladder cancer tends to rapidly progress within a few months. Given the success of immune checkpoint inhibitors in patients whose cancer grew after platinum-based chemotherapy, avelumab was recently evaluated in patients immediately after completing platinum-based chemotherapy if they had stable or responding cancer — in other words, before they progressed.
In such patients, avelumab extended survival regardless of tumor PD-L1 expression. The full results of this trial are expected to be presented soon and may lead to the use of avelumab in this ‘switch-maintenance’ space.
Newer clinical trials are also underway that aim to test the potential role of checkpoint inhibitors as first-line treatment for all patients with advanced bladder cancer. They are being evaluated in combinations with platinum-based chemotherapy and in combinations of two different checkpoint inhibitors, Sonpavde says.
- In one of these trials, combining atezolizumab with platinum-based chemotherapy extended the progression-free survival, but mature data to better evaluate survival are awaited.
- In another trial, the combination of 2 immune checkpoint inhibitors, durvalumab and tremelimumab, did not prolong survival compared to platinum-based chemotherapy.
However, data from other key trials, especially those evaluating the combination of immune checkpoint inhibitors nivolumab and ipilimumab, and the combination of platinum-based chemotherapy with PD1 inhibitors (pembrolizumab or nivolumab) are eagerly awaited.
Immune checkpoint inhibitors are also being evaluated in even earlier stages of bladder cancer. Trials are evaluating the efficacy of adjuvant (post-operative) immune checkpoint inhibitors after radical cystectomy surgery to remove muscle-invasive bladder cancer.
While one of the phase III trials did not show a benefit with adjuvant atezolizumab, other drugs are currently being studied. Moreover, phase III trials are also studying the use of checkpoint inhibitors as neoadjuvant (pre-operative) therapy before radical cystectomy for muscle-invasive bladder cancer, due to promising early results.
Finally, in non-muscle-invasive bladder cancer not responding to instillation of BCG into the bladder, pembrolizumab (given intravenously) was approved in January 2020. Confirmatory results from large trials are eagerly awaited. Every decision to treat patients with immune checkpoint inhibitors requires a careful consideration of efficacy and side effects (immune events such as diarrhea, lung inflammation, liver inflammation, endocrine effects, skin rash, kidney dysfunction and other rare events) so that the patient can make a fully informed decision.