Nivolumab has been found to extend lives of relapsed patients who had run out of therapy options. An immunotherapy drug hailed as a potential gamechanger in the treatment of cancer could soon offer new hope to patients with currently untreatable forms of the disease.
Nivolumab (Opdivo) was found to extend the lives of relapsed patients diagnosed with head and neck cancers who had run out of therapy options. After a year of treatment, 36% of trial patients treated with the drug were still alive compared with 17% of those given standard chemotherapy. Advanced head and neck cancers resistant to chemotherapy are notoriously difficult to treat and patients generally survive for less than six months.
Trial participants treated with nivolumab typically survived for 7.5 months, and some for longer. Middle-range survival for patients on chemotherapy was 5.1 months. The phase-three study, the last stage in the testing process before a new treatment is licensed, provided the first evidence of a drug improving survival in this group of patients.
Prof Kevin Harrington, from the Institute of Cancer Research, London, who led the British arm of the international trial, said:
“Nivolumab could be a real gamechanger for patients with advanced head and neck cancer. This trial found that it can greatly extend life among a group of patients who have no existing treatment options, without worsening quality of life. Once it has relapsed or spread, head and neck cancer is extremely difficult to treat. So it’s great news that these results indicate we now have a new treatment that can significantly extend life, and I’m keen to see it enter the clinic as soon as possible. Before it can be offered on the NHS, the treatment will have to be approved by the European Medicines Agency and the National Institute for Health and Care Excellence (Nice), which vets new therapies in England and Wales for cost-effectiveness."
Of the 361 patients enrolled in the trial, 240 were given nivolumab while the remaining 121 received one of three different chemotherapies. UK patients were assigned the chemotherapy drug docetaxel, the only treatment currently approved for advanced head and neck cancer by Nice. Patients whose tumours tested positive for the HPV virus, which is linked to cervical cancer and may be spread by oral sex, did especially well.
They typically survived for 9.1 months, compared with 4.4 months when treated with chemotherapy. The findings were simultaneously published in the New England Journal of Medicine and presented at the European Society for Medical Oncology (Esmo) conference in Copenhagen. In 2012 around 11,000 new cases of head and neck cancer were diagnosed in the UK and 3,300 Britons died from the disease.
The cancer can effect the lips, mouth, nasal cavity, back of the throat and voice box. More than half of patients relapse within three to five years. Nivolumab is one of a new class of antibody drugs called checkpoint inhibitors that help the immune system fight cancer. It works by blocking signals from tumour cells that stop the immune system attacking. The drug is already licensed for the treatment of advanced melanoma skin cancer and non-small-cell lung cancer in the UK.
However while Nice has backed its use on the NHS for melanoma it has so far refused to recommend making the drug freely available to lung cancer patients.
Prof Paul Workman, chief executive of the Institute of Cancer Research, said:
“Nivolumab is one of a new wave of immunotherapies that are beginning to have an impact across cancer treatment. This phase-three clinical trial expands the repertoire of nivolumab even further, showing that it is the first treatment to have significant benefits in relapsed head and neck cancer. “We hope regulators can work with the manufacturer to avoid delays in getting this drug to patients who have no effective treatment options left to them.”
Nivolumab and kidney cancer
In another study, combining nivolumab with another drug shrank tumours in advanced kidney cancer patients. Immunotherapy works by harnessing the immune system to destroy cancer cells.
About 12,000 people are diagnosed with kidney cancer in the UK each year and an average of 12 people die from the disease each day.
Peter Waite has kidney cancer. Peter was able to continue working as a motor technician while receiving immunotherapy treatment for cancer
"I feel a bit of a fraud having terminal cancer because I haven't been in pain at all," says Peter Waite, 64, from Hertfordshire.
"There's been nothing negative about it for me and I feel a bit embarrassed really."
Peter started receiving combined immunotherapy (nivolumab and ipilimumab) in a clinical trial in early 2015 after doctors discovered he had a type of renal cancer several years after recovering from kidney and lung cancer. He was told he probably had three to five years left. Instead of being treated with chemotherapy, he spent four months receiving both immunotherapy drugs and experienced virtually no side effects, allowing him to continue working as a motor technician throughout his treatment.
Scans of his kidney and lungs show that one of his tumours has shrunk and two others have not shown any further growth. He is no longer taking the drugs and is being monitored every 12 weeks with scans.
Mr Waite said his daughters have teased him about being a guinea pig - and considered buying him some hay.
"I'm a very upbeat sort of bloke and I've been very lucky," he says.
"I feel very privileged to have had the opportunity to go on the trial."
As yet, nivolumab has only been approved for treating skin cancer and in June it became one of the fastest medicines ever approved for NHS use, in combination with ipilimumab, for the same cancer.
Nivolumab and ipilimumab both work by interrupting the chemical signals that cancers use to convince the immune system they are healthy tissue.
Prof Kevin Harrington of the Institute of Cancer Research and consultant at the Royal Marsden Hospital in London, who led the head and neck cancer trial, said nivolumab could be a real "game changer" for patients with advanced head and neck cancer.
This trial found that it can greatly extend life among a group of patients who have no existing treatment options, without worsening quality of life. Once it has relapsed or spread, head and neck cancer is extremely difficult to treat. So it's great news that these results indicate we now have a new treatment that can significantly extend life, and I'm keen to see it enter the clinic as soon as possible."
Prof Paul Workman, chief executive of The Institute of Cancer Research, said nivolumab was one of a new wave of immunotherapies that were beginning to have an impact across cancer treatment. He added:
"We hope regulators can work with the manufacturer to avoid delays in getting this drug to patients who have no effective treatment options left to them."
Nivolumab (nye vol' ue mab), marketed as Opdivo, is a humanized IgG4 anti-PD-1 monoclonal antibody used to treat cancer.
Nivolumab works as a checkpoint inhibitor, blocking a signal that would have prevented activated T cells from attacking the cancer, thus allowing the immune system to clear the cancer. It was discovered at Medarex, developed by Medarex and Ono Pharmaceutical, and brought to market by Bristol-Myers Squibb (which acquired Medarex in 2009) and Ono.
As of April 2016, nivolumab was used as a first line treatment for inoperable or metastatic melanoma in combination with ipilimumab if the cancer does not have a mutation in BRAF (gene), as a second-line treatment following treatment with ipilimumab and if the cancer has a mutation in BRAF, with a BRAF inhibitor, as a second-line treatment for squamous non-small cell lung cancer, and as a second-line treatment for renal cell carcinoma.
It had not been tested in pregnant women but based on the mechanism of action and animal studies, is probably toxic to the fetus; it is not known if it is secreted in breast milk. Side effects include severe immune-related inflammation of the lungs, colon, liver, kidneys, and thyroid, and there are effects on skin, central nervous system, the heart, and the digestive system.
Mechansim of action
Nivolumab acts by blocking a negative regulator of T-cell activation and response, thus allowing the immune system to attack the tumor.
This is an example of immune checkpoint blockade. PD-1 is a protein on the surface of activated T cells. If another molecule, called programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), binds to PD-1, the T cell becomes inactive. This is one way that the body regulates the immune system, to avoid an overreaction. Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor. Nivolumab blocks PD-L1 from binding to PD-1, allowing the T cell to work. PD-L1 is expressed on 40–50% of melanomas and has limited expression otherwise in most visceral organs with the exception of respiratory epithelium and placental tissue.