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Nivolumab Bladder Cancer Fda Approval

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byMike Bassett, Staff Writer, MedPage Today August 20, 2021

The FDA has approved nivolumab as an adjuvant therapy for patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status, Bristol Myers Squibb announced.

Nivolumab becomes the first PD-1 inhibitor in UC with an indication in the adjuvant setting. Approval was based on results from the phase III CheckMate-274 trial.

“This approval is a major milestone for patients who have undergone major surgery to remove the bladder or parts of the urinary tract and are in need of additional treatment approaches that can help reduce the risk of their UC returning,” said primary investigator Matthew Galsky, MD, of the Icahn School of Medicine at Mount Sinai in New York City, in a press release.

“Nivolumab provides a new FDA-approved treatment shown to reduce the risk of disease recurrence or death based on the safety and efficacy findings from CheckMate-274, and has the potential to become a new standard of care option in this setting,” he added.

The trial compared a 240-mg dose of nivolumab in 353 patients or placebo in 356 patients. Patients treated with nivolumab achieved a median disease-free survival of 20.8 months versus 10.8 months with placebo, representing a 30% reduction in the risk for disease recurrence or death .

Nivolumab Approved For Locally Advanced Or Metastatic Bladder Cancer

The US Food and Drug Administration has approved intravenous nivolumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.1

This indication is approved under accelerated approval based on tumor response rate and duration of response. Verification and description of clinical benefit in confirmatory trials may be needed for continued approval for this indication.

Most people dont know how common bladder cancer is and that it is the fifth most diagnosed cancer, Stephanie Chisolm, director of Education and Research at Bladder Cancer Advocacy Network, said in a press release. This approval is another exciting step forward for the bladder cancer community and provides needed hope to patients and their families.

The recommended dose and schedule of nivolumab for urothelial carcinoma is 240 mg administered over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

The most common adverse events occurring in 20% of patients or more are asthenia/fatigue, lymphopenia, anemia, musculoskeletal pain, decreased appetite, and nausea. The most frequent grade 3 to 4 adverse events are asthenia/fatigue, urinary tract infection, lymphopenia, and anemia.

Reference

Opening The Door For Other Potential Treatments

Another checkpoint inhibitor, atezolizumab , was approved to treat bladder cancer last year.

The approval of atezolizumab opened the door for other checkpoint inhibitors to be tested in bladder cancer because it confirmed that bladder cancer cells can be recognized by the immune system, said Dr. Apolo.

In addition to nivolumab and atezolizumab, she noted, several other checkpoint inhibitors, such as pembrolizumab , avelumab, and durvalumab have shown similar activity in patients with bladder cancer that no longer responds to platinum-containing chemotherapy.

Although we do see responses, it is only in a small subset of patients. In order to improve upon this, were focusing on immunotherapy combinations, Dr. Apolo continued. For instance, she is leading a clinical trial that will test the combination of nivolumab plus a targeted therapy, cabozantinib, with or without the addition of another checkpoint inhibitor, ipilimumab , in patients with advanced or metastatic bladder cancer.

And several clinical studies are exploring the use of checkpoint inhibitors in earlier stages of bladder cancer, including as a first-line treatment for patients with metastatic disease, as an adjuvant therapy for patients with tumors that have spread locally into the surrounding muscle, and even for patients with very early-stage tumors that have not spread to the muscle.

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Fda Approves Nivolumab As First Adjuvant Treatment For High

On August 19, the U.S. Food and Drug Administration approved the PD-1blocking antibody nivolumab for adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection. Nivolumab is the first FDA approval for adjuvant treatment of patients with high-risk urothelial carcinoma.

The FDAs decision is based on the multicenter CheckMate 274 trial evaluating nivolumab as an adjuvant treatment in patients within 120 days of radical resection of urothelial carcinoma originating in the bladder or upper urinary tract and who were at high risk of recurrence. Patients were randomly assigned to receive 240 mg of nivolumab or a placebo by intravenous infusion every 2 weeks until recurrence or until unacceptable toxicity for a maximum treatment duration of 1 year.

Results showed a statistically significant improvement in disease-free survival in patients on the nivolumab arm compared with the placebo arm. The median disease-free survival was 20.8 months versus 10.8 months, respectively. The median disease-free survival was not reached for patients with tumors expressing PD-L1 1% in the nivolumab arm. Meanwhile, patients with tumors expressing PD-L1 1% in the placebo group had a disease-free survival of 8.4 months.

The recommended nivolumab dosage for adjuvant treatment of urothelial carcinoma is 240 mg every 2 weeks or 480 mg every 4 weeks. For full prescribing information, visit accessdata.fda.gov.

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The FDA has granted regular approval to nivolumab as adjuvant therapy for patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection. This is the first time the FDA has approved an adjuvant treatment for patients with high-risk urothelial carcinoma. Nivolumab had previously been granted accelerated approval for advanced and metastatic urothelial cancer. “In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab or placebo,” wrote Dean F. Bajorin, MD, the Frederick R. Adler Senior Faculty Chair and a medical oncologist specializing in genitourinary tumors at Memorial Sloan Kettering Cancer Center, and colleagues, in their abstract of the results of the CHECKMATE-274 study , on which the regular approval was based.

The recommended dose of nivolumab for adjuvant treatment of urothelial carcinoma is 240 mg every 2 weeks or 480 mg every 4 weeks.

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Fda Approves Nivolumab For Bladder Cancer

Drawing of locally advanced bladder cancer, which has spread into the muscle and fat layers lining the bladder.

On February 2, the Food and Drug Administration granted accelerated approval to nivolumab for the treatment of some patients with urothelial carcinoma, the most common type of bladder cancer. This makes nivolumab the second immune checkpoint inhibitor to be approved for the treatment of bladder cancer.

Approximately half of patients with bladder cancer do not respond to their initial, or first-line, therapy, and only 10%15% of those patients respond to second-line chemotherapy. The nivolumab approval is for patients with locally advanced or metastatic bladder cancer whose disease has gotten worse during or after first-line, adjuvant or neoadjuvant therapy with platinum-containing chemotherapy.

These patients do not have a lot of treatment options. Theres a tremendous need for therapies that work in this setting, said Andrea Apolo, M.D., in the Genitourinary Malignancies Branch of NCIs Center for Cancer Research.

By binding to a protein called PD-1 on the surface of T cellsa type of white blood celland preventing it from interacting with the PD-L1 protein on cancer cells, nivolumab releases the brakes on the immune system, allowing T cells to attack cancer cells.

The approval of nivolumab is an affirmation of the important role that immunotherapy plays in the treatment of advanced bladder cancer, Dr. Apolo said.

Clinical Study Of Nivolumab

The approval was based on the results of a phase II clinical trial of 270 patients with unresectable locally advanced or metastatic bladder cancer that had worsened or come back after treatment with at least one platinum-based chemotherapy regimen.

All patients in the trial were treated with the same dose of nivolumab. Of the 265 patients that could be evaluated, 52 had a confirmed objective response, meaning their tumors shrank measurably. Of those patients, 46 had a partial response and six had a complete response.

This is an improvement compared with the 10-15% objective response rate historically observed among patients treated with second-line chemotherapy, the investigators noted.

In other clinical studies, expression of PD-L1 by tumor cells has been used to predict patient response to treatment with checkpoint inhibitors. The research team found that treatment with nivolumab produced measurable responses among patients with all levels of PD-L1 expression. For example, 28% of patients whose tumors were considered to have the highest PD-L1 expression and 16% of patients whose tumors had the lowest PD-L1 expression had an objective response.

However, it is not surprising that some patients with low PD-L1 expressing-tumors had responses to nivolumab, said Dr. Apolo.

There are a lot of variables with the PD-L1 test, and the immune system is very dynamic, she explained. We cant really say that PD-L1 is a perfect biomarker to predict response.

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The Us Food And Drug Administration Decision Means Nivolumab Is Now An Approved Treatment For Six Types Of Cancer

Use of the immunotherapeutic nivolumab was recently expanded by the U.S. Food and Drug Administration to include the treatment of certain patients with bladder cancer.

Under the expanded approval, nivolumab is intended for treating patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed despite treatment with platinum-based chemotherapy or whose disease progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

Urothelial carcinomas begin in urothelial cells that line the inside of the bladder.According to the National Cancer Institute, they account for more than 90 percent of bladder cancer cases diagnosed in the United States. In 2017, this is predicted to translate into more than 71,000 new cases of urothelial carcinoma.

With a five-year relative survival rate of just 5 percent, new treatment options are urgently needed for metastatic bladder cancer.

The approval of nivolumab for urothelial carcinoma was based on results from a phase II clinical trial, according to the FDA announcement. In brief, the results showed that 19 percent of the 270 patients who received nivolumab had tumor shrinkage for a median of 10.3 months. Of the 53 patients who had tumor shrinkage, 7 had complete tumor shrinkage and 46 had partial shrinkage.

The FDA approval was rendered on Feb. 2, 2017.

Checkpoint Inhibitors And Bladder Cancer

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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 , explained Andrea B. Apolo, M.D., who heads the Bladder Cancer Section in NCIs Center for Cancer Researchs Genitourinary Malignancies Branch.

But we still needand are awaitingthe 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 , targets PD-1.

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Approval In Advanced Disease

Opdivo,, which is a programmed cell death receptor1 inhibitor was the second immunotherapy approved to treat advanced bladder cancer. The FDA also approved Tecentriq , which acts as a programmed cell death ligand1 inhibitor, in May 2016.

The approval was based on a study in 270 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression during or following platinum-containing chemotherapy, or whose disease progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The objective response rate following Opdivo treatment was 19.6% 7 patients had complete responses, and 46 had partial responses. The estimated median duration of response was 10.3 months. The FDA notes that some responses were ongoing at data cutoff.

For this Opdivo, application, the FDA granted a breakthrough therapy designation and priority review status. The application was approved about 1 month ahead of schedule.

Reference:

About The Phase Iii Checkmate 274 Clinical Trial

The trial evaluated the use of post-surgery Opdivo in 709 patients with muscle-invasive urothelial carcinoma of the bladder, ureter, or renal pelvis who underwent radical surgery with or without pre-surgery cisplatin-based chemotherapy. Patients with a high risk for recurrence based on the tumor stage at surgery were treated with either Opdivo or placebo every other week for 1 year and directly compared.

Opdivo treatment significantly delayed the time to cancer recurrence. Opdivo treated patients survived on average 21 months without cancer recurrence compared to only 11 months for those receiving placebo. The benefit from Opdivo treatment was irrespective of PD-L1 status. In patients whose tumors had a PD-L1 expression of 1% or higher Opdivo immunotherapy resulted in a 45% reduction in the risk of disease recurrence or death

Overall therapy was well tolerated, and the most common treatment-related side effects were diarrhea, colitis, and pneumonitis.

Opdivo is the first immune therapy to be used in the adjuvant setting that provides clinically meaningful improvement in disease-free survival for patients with high-risk muscle-invasive urothelial carcinoma after radical surgery with curative intent. This trial led to FDA approval of Opdivo for use as adjuvant treatment of patients with urothelial carcinoma who are at high risk of cancer recurrence after undergoing surgical removal of their cancer in August 2021.

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Bladder Cancer And Hodgkin Lymphoma Fda Approvals Expand Immunotherapys Reach

Last week, the U.S. Food and Drug Administration increased the number of cancer types for which immunotherapeutics known as checkpoint inhibitors are an approved treatment option. On Tuesday, the agency expanded the use of nivolumab to include the treatment of certain patients with Hodgkin lymphoma. The following day, it approved a new immunotherapeutic known as atezolizumab for certain patients with bladder cancer, a disease for which there have been no new treatments approved in more than three decades.

Immunotherapeutics work by harnessing the power of a patients immune system to fight cancer the way it fights disease-causing microbes such as the influenza virus.

Nivolumab and atezolizumab work in different ways to release a brake called PD-1 on cancer-fighting immune cells called T cells. Once the PD-1 brake is released, the T cells are able to carry out their natural function and can destroy cancer cells.

Nivolumab targets PD-1 itself, preventing the brake from being triggered. Atezolizumab targets PD-L1, which is one of two proteins that can attach to PD-1, triggering its brake function. By targeting PD-L1, atezolizumab prevents this protein from triggering the PD-1 brake on T cells, it also prevent PD-L1 from triggering another brake on T cells called B7.1. Atezolizumab is the first PD-L1 inhibitor to be approved by the FDA.

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Fda Approves Adjuvant Nivolumab In Bladder Cancer

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The FDA has approved nivolumab for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status, Bristol Myers Squibb announced in a news release.1

The approvals basis comes from the randomized, double-blind phase 3 CheckMate -274 trial , which evaluated nivolumab, 240 mg in 353 patients vs 356 patients receiving placebo.2 Patients who received nivolumab had a median disease-free survival of 20.8 months vs 10.8 months in the placebo arm.

In the release, Checkmate -274 primary investigator Matthew Galsky, MD, hailed the approval as a major milestone for patients who have undergone major surgery to remove the bladder or parts of the urinary tract and are in need of additional treatment approaches that can help reduce the risk of their UC returning.

Nivolumab provides a new FDA-approved treatment shown to reduce the risk of disease recurrence or death based on the safety and efficacy findings from CheckMate -274, and has the potential to become a new standard of care option in this setting, added Galsky, professor of medicine, director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, New York.

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Fda Approves Nivolumab For Urothelial Carcinoma

The FDA has granted an accelerated approval to nivolumab as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy, based on findings from a phase II CheckMate-275 study.

Jonathan E. Rosenberg, MD

The FDA has granted an accelerated approval to nivolumab as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy, based on findings from a phase II CheckMate-275 study.

In the study, which was presented at the 2016 ESMO Annual Meeting, the objective response rate was 19.6% for nivolumab in patients with platinum-refractory metastatic urothelial carcinoma. The complete response rate was 3%. Across the 270-patient study, the median progression-free survival was 2.0 months and the median overall survival was 8.74 months.

A nearly 20% response rate in advanced and metastatic bladder cancer is extremely encouraging and clinically meaningful in this patient population, Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, said in a statement.

The open-label study enrolled 270 patients with metastatic or unresectable urothelial carcinoma. Patients had received a platinum-based agent in the metastatic setting or were within one year of neoadjuvant/adjuvant platinum therapy.

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