NIVOLUMAB-IPILIMUMAB COMBINATION FOR RENAL CANCER APPROVED BY EMA

There has been a change of mind in Europe about the use of an immunotherapy combination for first-line treatment of kidney cancer.

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy), both from Bristol-Myers Squibb, was shown in a phase 3 trial to improve survival significantly when compared to the standard of care, sunitinib (Sutent, Pfizer), in patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC).

When these results, from the CheckMate 214 trial, were presented at the 2017 European Society of Medical Oncology, experts predicted that they would change the paradigm for first-line treatment of kidney cancer and that the immunotherapy combination would become a new standard of care. The study was later published online in the New England Journal of Medicine. 

These results led to the approval in the United States in April 2018 of the combination of nivolumab and ipilimumab for use as an initial treatment for advanced RCC that is of intermediate or poor risk.

However, in Europe, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a negative opinion for this indication in July 2018 after reviewing the same clinical data.

Now, after a re-examination that was requested by the company, the CHMP has reversed its stance and has issued a positive opinion for this indication, which opens the door for approval of this indication in the European Union.

The CHMP explains its change of mind in a question and answer document.

It notes that previous studies have already demonstrated benefit with nivolumab alone in patients with previously treated kidney cancer. Although the CheckMate 214 trial involved a different patient population (those with previously untreated kidney cancer) and showed improved survival with the combination of the two immunotherapies, "there was no evidence showing if ipilimumab had contributed to these results and if so, how much."

At the same time, it was clear that the combination of the two immunotherapies resulted in more side effects than are seen with nivolumab alone. Therefore, at that time (July 2018, when it issued the negative opinion), the CHMP considered that the combination could not be approved because of the lack of knowledge of the contribution of ipilimumab.

During re-examination of the data, which was requested by the manufacturer, the CHMP looked again at all the data and consulted a group of cancer experts and patients with cancer.

On re-examination, the CHMP considered that the results from CheckMate-214 showed a clinically important increase in patients' survival with the combination in comparisoin to sunitinib and that the side effects were acceptable. Although the precise contribution of ipilimumab was not clear, the CHMP reassessed data from other nonclinical and clinical studies, including studies in other cancer types, and thought that the benefit of ipilimumab in the combination has been sufficiently demonstrated. The CHMP was of the opinion that the benefits of the combination largely outweigh its risks, and therefore recommended granting the change to the marketing authorization.

However, the CHMP also noted that the manufacturer must conduct a study to determine the precise contribution of ipilimumab in the combination and if the risks could be further minimized.

Also Change of Mind About Blintumomab

The CHMP also changed its mind about another product that received a negative opinion at that time.

The CHMP has now recommended an extension of therapeutic indication for blinatumomab (Blincyto, Amgen) in patients with residual cancer cells in the body after previous treatment. The CHMP re-examined the negative opinion for this medicine that it adopted in July 2018.

Blinatumomab is used in the treatment of B-precursor acute lymphoblastic leukemia (ALL). It has been available in Europe since November 2015.

The latest decision concerned an extension of the use of this drug to patients with ALL who had residual cancer cells in the body after previous treatment.

In support of the application for this extension of use, the company presented data from a main study in 116 patients with residual cancer cells who were treated with blinatumomab. That study assessed the number of patients who no longer had measurable residual disease after undergoing one treatment cycle.

When it initially considered these data, the CHMP noted that although the drug helped to reduce the amount of residual cancer cells in many patients, there was no strong evidence that it led to improved survival.

Given this uncertainty, the CHMP was of the opinion that the benefits of blinatumomab in patients with residual B-precursor ALL cells did not outweigh its risks. The CHMP therefore issued a negative opinion, it explains in a question-and-answer document.

However, at the request of the company, the CHMP re-examined the data. The CHMP says it reevaluated all the data and consulted a group of experts in cancer treatments.

"The CHMP agreed with the expert group's conclusion that, although there is no strong evidence of patients living longer, the available data from the main study indicate a good response to blinatumomab, with around 78% of patients not having measurable residual cancer cells after treatment. The Committee also considered that patients with minimal residual disease are at high risk of the disease coming back and have few treatment options," it explains.

Therefore, the CHMP concluded that the benefits of blinatumomab outweigh its risks, and recommended granting the change to the marketing authorization to include the extended use.

The CHMP requested the company to provide further data from ongoing studies as they become available.

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