Checkpoint inhibition in head and neck tumors

The results of a 2018 comparative study were as good for inhibitors as those achieved with aggressive chemotherapy. The use of these drugs is currently being tested in the so-called ADRISK study at 13 ENT clinics in Germany.

Large study to evaluate inhibitor use until 2022

Head and neck cancer can be successfully treated with drugs that strengthen the body's immune defense against tumors. Last year, the results of a comparative study were as good as those achieved with aggressive chemotherapy. The use of these drugs is currently being tested in the so-called ADRISK study at 13 ENT clinics in Germany.

Approximately 17,000 people suffer from cancer in the oral cavity, throat, nose or larynx in Germany every year. The tumors are often the result of long-term alcohol or cigarette consumption. However, they are also increasingly caused by chronic infections with human papillomaviruses (HPV).

Many of the tumors are discovered too late to be cured by surgery alone. "Due to their extent or proximity to vital structures, they can often only be removed by extensive surgery in combination with radiotherapy," explained Professor Andreas Dietz, Director of the Department of Otolaryngology at the Leipzig University Hospital, Germany.

Many patients, therefore, receive radiation and/or chemotherapy with cytostatics after surgery, or, if it is no longer possible to operate, they receive what is known as primary radiochemotherapy. This is a combination of radiation therapy and chemotherapy with cytostatics. If the tumor recurs, the doctors will always try to remove it surgically. However, due to distant metastases, it is often necessary to understand that only life-prolonging palliative measures can be implemented. So far, chemotherapy has been used in such cases.

Checkpoint inhibitors break through tumor protection mechanisms

In the meantime, checkpoint inhibitors are increasingly being used as immunotherapy. In contrast to cytostatic drugs, these monoclonal antibodies do not directly attack cancer cells. Rather, they target a checkpoint of the immune system: the PD1 protein. It is located on the surface of T cells, which are the most important attackers of the immune system against cancer cells. The PD1 protein acts as a brake. It is supposed to prevent overzealous T cells from attacking the body's own cells.

Many cancer cells make use of this mechanism. They bind the PD1 protein with a ligand (PD-L1) and thus protect themselves against T cell attacks. "The cancer cells evade the immune defense by countering the immune cells with a kind of molecular stop sign," Professor Dietz explained further. "If these stop signals come into contact with suitable receptors on the immune cells’ surfaces, these are deactivated and the immune defense comes to a standstill. However, specific antibodies against the tumor's own stop signals - checkpoint inhibitors - can break through this blockade and release the T cells from this bondage by blocking either PD-1 or PD-L1. The tumors are then released by the T-cells."

The current study is promising

Checkpoint inhibitors were initially used to treat skin cancer and kidney cancer. "They will soon become an integral part of the treatment of head and neck tumors," said Professor Dietz. According to the expert, the breakthrough was achieved in 2016 with the CHECKMATE 141 study (nivolumab) in second-line therapy and in 2018 with the KEYNOTE-048 study (pembrolizumab) in first-line therapy, the results of which were presented last October at the European Cancer Congress (ESMO 2018) in Munich.

The study included patients with head and neck cancer who had metastasized or relapsed after treatment. Some of the patients received the current standard treatment. It consists of aggressive chemotherapy with three cytostatic agents ("EXTREME regimen") plus an antibody against cancer growth. A second group was treated only with the PD-1 inhibitor pembrolizumab.

"In the run-up, there were strong doubts as to whether monotherapy with a PD-1 inhibitor could actually beat the very potent, but also toxic, triple-combination of the EXTREME regimen," reported Professor Dietz. However, the results have exceeded expectations. More patients responded to chemotherapy than to pembrolizumab (36.1% versus 23.3%). However, the effect of pembrolizumab lasted 20.0 months compared to 4.5 months for more than five times as long. In addition, patients were spared the severe side effects of chemotherapy.

According to Professor Dietz, the study will lead to more patients being offered treatment with a checkpoint inhibitor before or in combination with chemotherapy in the future. Currently, numerous clinical studies are investigating the different possible applications of checkpoint inhibitors, in particular in combination with surgical therapy. This also includes the ADRISK study led by Professor Dietz, which is currently testing whether the checkpoint inhibitor pembrolizumab improves treatment results if it is used together with radiation and chemotherapy after cancer surgery. This study in implementing tests at 13 ENT clinics in Germany and involves 240 patients. The results are expected in August 2022.