FDA Approves Three Immunotherapy Drugs for Patients with Bladder Cancer

May 15, 2017, by NCI Staff

A CT scan from a patient with bladder cancer, showing disease-related thickening of the bladder wall.
Credit: Wikimedia Commons, CC-BY-SA-4.0

The Food and Drug Administration (FDA) in recent weeks has approved three immunotherapy drugs for bladder cancer, bringing the total number of approved immunotherapies for this disease to four. Known as checkpoint inhibitors, all four drugs work by “releasing the brakes” on the immune system and allowing immune cells to attack tumors.

In the most recent approval, FDA on May 9 granted accelerated approval for avelumab (Bavencio®) for the treatment of some patients with urothelialcarcinoma, the most common type of bladder cancer. The approval is for patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or after treatment with platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvantchemotherapy.

Prior to that, on May 1, the FDA granted accelerated approval to durvalumab (Imfinzi™)for the same indication as avelumab.

And on April 17, the FDA granted atezolizumab (Tecentriq®) an accelerated approval as a first-line treatment for patients with locally advanced or metastatic urothelial carcinoma who are not eligible to receive cisplatin-based chemotherapy. (Many patients with advanced forms of urothelial carcinoma are not candidates for cisplatin-based chemotherapy because they have health problems, including impaired kidney function, hearing loss, or heart failure.)

New Atezolizumab Results

The atezolizumab approval is an expansion of an earlier approval for bladder cancer. In 2016, FDA approved the drug for patients with locally advanced or metastatic urothelial carcinoma that had gotten worse during or after treatment with cisplatin, which is known as the second-line setting.

However, Genentech, the drug’s maker, said in a May 9 statement that, in a large clinical trial, atezolizumab did not meet its primary endpoint of improving overall survival in the second-line setting. The results are from the IMvigor211 study, which the company said was intended to be the confirmatory study to convert accelerated approval to full approval in the United States.

“The results are disappointing, but we still need to examine the data, which have not been publicly released yet,” said Andrea B. Apolo, M.D., who heads the Bladder Cancer Section in NCI’s Center for Cancer Research’s (CCR) Genitourinary Malignancies Branch.

“Atezolizumab is an active agent in patients with platinum-refractory advanced urothelial carcinoma,” Dr. Apolo continued. Even if the checkpoint inhibitor is not superior to second-line chemotherapy, atezolizumab has a favorable toxicity profile and may be a good alternative if the treatments are equivalent in terms of overall survival, she added.

Checkpoint Inhibitors and Bladder Cancer

Long-term survival for people diagnosed with advanced bladder cancer is poor, with approximately 5% of patients with metastatic bladder cancer surviving for 5 years or more.

Checkpoint inhibitors have shown activity in patients with metastatic bladder cancer in both the second-line setting and the first-line setting (before chemotherapy), explained Dr. Apolo.

“But we still need—and are awaiting—the results of ongoing randomized trials comparing checkpoint inhibitors and chemotherapy in the first-line setting for patients with metastatic bladder cancer,” she continued. “The results will allow us to adequately compare patient outcome in terms of survival and quality of life with these therapies.”

The drugs covered by these approvals all target a protein known as PD-L1 that is expressed at high levels on some cancer cells. Normally, binding of PD-L1 to its receptor protein, PD-1, on immune cells tamps down immune activity. By preventing the interaction between PD-L1 and PD-1, they allow the immune system to be more active against tumor cells that express PD-L1.

The other checkpoint inhibitor approved by the FDA for the treatment of patients with bladder cancer, nivolumab (Opdivo®), targets PD-1.

Approval of Avelumab

The approval for avelumab was based on data on objective response—that is, a reduction in the size of tumors—from a nonrandomized 242-patient clinical trial. At 13 weeks after initiating avelumab treatment, 13.3% of patients experienced a tumor response, the FDA reported. At 6 months, that figure increased to 16.1%. The median time it took patients to achieve a tumor response was 2 months, with responses lasting from 1.4 months to more than 17 months.

Adverse reactions to avelumab led to the deaths of 6% of patients in the trial. In addition, according to the FDA, 41% of patients had serious adverse reactions, including urinary tract infection and secondary bacterial infections of the blood, blood in the urine and urinary tract, and intestinal obstruction. The most common side effects of the treatment included fatigue, musculoskeletal pain, and nausea.

In April, avelumab, which is manufactured by EMD Serono, became the first FDA-approved drug for the treatment of Merkel cell carcinoma.

Approval of Durvalumab

The basis for the drug’s approval was a single-arm phase I/II clinical trial with 182 patients whose disease had progressed after treatment with platinum-containing chemotherapy. The objective response rate in the study was 17%, and the median duration of response has not yet been reached. Medimmune, an arm of AstraZeneca, the drug’s maker, sponsored the trial.

The FDA also approved a complementary diagnostic called the VENTANA PD-L1 (SP263) Assay, which physicians may use to measure the expression levels of PD-L1 in a patient’s tumor. However, durvalumab is approved for use regardless of a patient’s PD-L1 status.

An analysis of response according to PD-L1 levels in the patients’ tumors showed objective response rates of approximately 26% in 95 patients with a high PD-L1 score and of 4% in 73 patients with a low or negative PD-L1 score.

Common side effects of durvalumab included fatigue, musculoskeletal pain, and constipation. Infection and immune-related side effects were also reported.

Durvalumab is being evaluated as a first-line therapy alone and in combination with tremelimumab in the phase III DANUBE trial .

New Atezolizumab Approval

The expanded approval of atezolizumab as a first-line treatment was based on the results of the IMvigor210 (Cohort 1) trial, which was sponsored by Genentech. Among 119 patients in the phase II study who received atezolizumab, the overall response rate was 23.5%, including complete responses in 6.7% of the patients and partial responses in 16.8% of the patients. The median duration of response to the drug has not been reached.

The most common side effects of treatment with atezolizumab were fatigue, diarrhea, and severe itching, or pruritus. The treatment may also cause immune system-related side effects. Nine patients had side effects that led them to stop the drug.