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Bladder carcinoma in patients that can't tolerate chemotherapy: treatment with Pembrolizumab, a PD-1 blocking monoclonal antibody

A treatment harnesses the immune system to shrink tumors in bladder cancer patients that cannot take the most effective chemotherapy.
These are the findings of a clinical trial led by researchers at NYU Langone Medical Center and its Perlmutter Cancer Center and just presented at the annual meeting of the European Society for Medical Oncology ( ESMO ).

The new study found that injections of the experimental agent Pembrolizumab ( Keytruda ) shrank tumors by at least one third in 24% of patients. Of those, 6% saw their tumor lesions disappear.

All patients in the study were unable to take the current standard of care, Cisplatin, which is a chemotherapy that prevents tumor cells from repairing damage to their DNA. Used widely since the 1970s, Cisplatin extends survival to slightly more than a year, but nearly half of bladder cancer patients, most of them elderly and ill, cannot take it because of its toxic effects on nerves and kidneys.

About 76,000 Americans will be diagnosed with bladder cancer in 2016, with men three times more likely than women to develop the disease.

While 67% of patients in the study experienced side effects linked to Pembrolizumab treatment, most were tolerable, including fatigue ( 14% ) as the most common along with itchy skin and diarrhea.
Five percent of patients in the study stopped therapy because of side effect severity.

When compared to chemotherapy, the side effect profile with Pembrolizumab was far less severe. In addition, 83% of those treated in the current trial had a response that lasted for at least six months, while responses to most chemotherapies are temporary.

Part of a new class of drugs known as checkpoint inhibitors, Pembrolizumab has been approved since 2014 for the treatment of head and neck squamous cell carcinoma, melanoma, and non-small cell lung cancer.
The current clinical trial, called KEYNOTE-052, was designed to enroll approximately 350 patients at 50 research centers in the United States and Europe, with the results from the first 100 patients included in the current, interim analysis.

The study results revolve around the immune system, which is designed to attack foreign organisms like bacteria, while leaving the body's healthy cells alone. To spare normal cells from immune attack, the system uses checkpoints, sensors on immune cells that turn them off when they receive the right signal.
The body recognizes tumors as abnormal, but cancer cells hijack checkpoints to turn off immune responses.

Among the most important checkpoints is a protein called programmed death receptor 1 ( PD-1 ), which is shut down by Pembrolizumab to make tumors visible again to the immune system.

Past studies have found that levels of PD-1, as well as of its signaling partners ( PD ligand 1 or PD-L1 ), vary dramatically across patients with bladder cancer. This has frustrated efforts to arrive at a consensus threshold for when doctors should recommend that a given patient receive Pembrolizumab.

Researchers analyzed responses to Pembrolizumab in two patient groups: one with PDL1 expressed in at least 1% of their immune and cancer cells, and a second with PD-L1 in at least 10% of their cells.
They found that 13.3% of patients with PD-L1 levels in at least 10% of their immune and cancer cells saw their tumors disappear compared to 6.3% in the group with 1% PD-L1 expression and 6% in the entire patient population.
The separation in results may point to the 10% cut-point as a good biomarker to select patients most likely to respond. ( Xagena )

Source: ESMO Congress, 2016