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FDA Approves Immunotherapy Drugs for Patients with Bladder Cancer

May 30, 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

Editor’s Note: This post, originally published May 15, has been updated to include new approvals of pembrolizumab (Keytruda®) for patients with bladder cancer.

The Food and Drug Administration (FDA) in recent weeks has approved four immunotherapy drugs for bladder cancer, bringing the total number of approved immunotherapies for this disease to five. 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 18 granted regular approval to pembrolizumab for the treatment of some patients with urothelial carcinoma, the most common type of bladder cancer. The approval is for patients with locally advanced or metastatic bladder cancer whose disease has progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy.

FDA also granted accelerated approval to pembrolizumab for patients with locally advanced or metastatic bladder cancer who are not eligible for cisplatin-containing chemotherapy.

On May 9 and May 1, FDA granted accelerated approvals for avelumab (Bavencio®) and durvalumab (Imfinzi), respectively, also for patients with locally advanced or metastatic bladder cancer whose disease has progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy.

And on April 17, 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.)

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 Andrea B. Apolo, M.D., who heads the Bladder Cancer Section in NCI’s Center for Cancer Research’s (CCR) Genitourinary Malignancies Branch.

“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.”

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

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

Two Pembrolizumab Approvals

The regular approval of pembrolizumab as a second-line therapy for bladder cancer was based on results of the KEYNOTE-045 study, which included patients with locally advanced or metastatic bladder cancer that had progressed on or after platinum-containing chemotherapy. In this multicenter, randomized clinical trial, pembrolizumab was associated with an improvement in median overall survival (of approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy.

The accelerated approval of pembrolizumab as a first-line therapy for bladder cancer was based on results from the KEYNOTE-052 study, a single-arm, open-label trial in 370 patients with locally advanced or metastatic bladder cancer who were not eligible for cisplatin-containing chemotherapy. With a median follow-up of 7.8 months, the response rate was approximately 29% and the median duration of response had not yet been reached.

The most common side effects in the two trials included fatigue, musculoskeletal pain, decreased appetite, nausea, and diarrhea.

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.

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.

However, Genentech, the drug’s maker, reported on May 9 that, in a large clinical trial, atezolizumab did not meet its primary endpoint of improving overall survival in this 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 Dr. Apolo.

“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.

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