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Withdrawal of Application to Change the EU Marketing Authorisation for Nivolumab and Ipilimumab

Intended extension of indication concerned metastatic non-small cell lung cancer that has not been previously treated
09 Mar 2020
Cancer Immunology and Immunotherapy;  Lung and other thoracic tumours

On 28 February 2020 the European Medicines Agency (EMA) informed that Bristol-Myers Squibb Pharma EEIG withdrew on 30 January 2020 its application for the use of nivolumab (Opdivo) and ipilimumab (Yervoy) in combination for the treatment of metastatic non-small cell lung cancer (NSCLC) that has not been treated previously.

Opdivo and Yervoy are cancer medicines. They contain the active substances nivolumab and ipilimumab, respectively. Opdivo has been authorised in the EU since June 2015. It is already used on its own to treat NSCLC in patients who have previously been treated with other cancer medicines. It is also used to treat melanoma, renal cell carcinoma (RCC), Hodgkin’s lymphoma, squamous cell cancer of the head and neck, and urothelial cancers. Yervoy has been authorised in the EU since July 2011. It is used to treat melanoma and RCC. Further information on current uses of Opdivo and Yervoy can be found on the EMA’s website.

The company applied for an extension of indication to add the use of Opdivo and Yervoy in combination for patients with previously untreated metastatic NSCLC and where the tumour does not have EGFR and ALK mutations.

In metastatic NSCLC, Opdivo and Yervoy are expected to work in the same way as they do in their existing indications. The active substances in these medicines, nivolumab and ipilimumab, are monoclonal antibodies. Nivolumab attaches to PD-1, which is found on T cells. Cancer cells can produce PD-L1 and PD-L2 that attach to PD-1 receptor and switch off the activity of the T cells, preventing them from attacking the cancer. By attaching to the receptor, nivolumab prevents PD-L1 and PD-L2 from switching off the T cells, thereby increasing the ability of the immune system to kill cancer cells. Ipilimumab attaches to and blocks the activity of CTLA-4, a protein that controls the activity of T cells. By blocking CTLA-4, ipilimumab activates T cells, which kill the tumour cells.

To support its application, the company presented the results of a study that involved 1,739 patients with previously untreated metastatic NSCLC. The study compared treatment with the combination of Opdivo and Yervoy, treatment with a combination of two platinum-based cancer medicines, and treatment with the two platinum-based medicines and Opdivo. The study endpoints were overall survival and progression-free survival.

The application was withdrawn after the EMA had evaluated the initial information from the company and had prepared questions for the company. After the Agency had assessed the company’s responses to the questions, there were still some unresolved issues.

Based on the review of the information and the company’s response to the Agency’s questions, at the time of the withdrawal, the Agency had some concerns and its provisional opinion was that treatment with Opdivo and Yervoy in combination could not have been authorised for the treatment of metastatic NSCLC that has not been treated previously.

During the study, the way it was set up changed substantially several times and there were concerns about how the company handled the data. In addition, there were inconsistencies in the study results for different groups of patients. Therefore, at the time of the withdrawal, the Agency’s opinion was that it was not possible to come to reliable conclusions on effectiveness and, as a result, the Agency could not conclude that the benefits of Opdivo and Yervoy as combination in the treatment of metastatic NSCLC outweighed the risks.

In its letter notifying the Agency of the withdrawal of application, the company stated that the withdrawal was based on the fact that the Agency could not conclude that there was a positive benefit-risk balance for the medicines in the treatment of metastatic NSCLC that has not been treated previously.

The company informed the Agency that there are no consequences for patients in clinical trials using Opdivo and Yervoy. There are no consequences on the use of either medicine in their authorised uses.

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