Europe OKs First PD Inhibitor, Nivolumab

Zosia Chustecka


April 24, 2015

Nivolumab (Opdivo, Bristol-Myers Squibb Company) becomes the first programmed-death (PD) immune checkpoint inhibitor immunotherapy to be recommended for approval in Europe.

The European Medicines Agency has recommended approval of the drug for use as first-line treatment and also for use in previously treated patients with advanced (unresectable or metastatic) melanoma.

This is a broader indication than one for which the drug was already approved in the United States, where the approval for nivolumab stipulates that it is for use after treatment with another immune checkpoint inhibitor, ipilimumab (Yervoy, Bristol-Myers Squibb Company).

The European positive opinion for first-line use is based on a clinical trial reported in November 2014 at the Society of Melanoma Research meeting and simultaneously published online in the New England Journal of Medicine.

This trial was conducted in 418 patients with previously untreated metastatic melanoma (and without BRAF mutations). It compared nivolumab with dacarbazine (multiple brands), a chemotherapy that is often used as a standard of care.

The results showed a 1-year survival rate of 72.9% with nivolumab vs 42.1% with chemotherapy (dacarbazine), with a hazard ratio of 0.42 (P < .0001).

This study, known as CheckMate 066, was conducted in Australia, Canada, Europe, Israel, and South America, because these are areas where dacarbazine is often used as the standard of care.

Principal investigator Georgina Long, MD, PhD, from the Melanoma Institute Australia, at the University of Sydney, who presented the results at the meeting, said: "Nivolumab first-line represents a potential new standard of care," and she urged regulatory authorities to approve the drug for first-line use.

Different Situation in US

The situation is a little different in the United States, where ipilimumab is approved for first-line use in metastatic melanoma. To obtain an approval for nivolumab for first-line use in the United States, Bristol-Myers Squibb (which markets both drugs) would have to conduct a head-to head comparison.

This has just been reported with another PD inhibitor, pembrolizumab (Keytruda, Merck & Co, Inc), which has a mechanism of action similar to that of nivolumab.

Pembrolizumab showed superior results when compared with ipilimumab when used as initial therapy in the KEYNOTE-006 study, the first head-to-head trial of the two different types of immune checkpoint inhibitors. This study was stopped early last month and was presented in full earlier this week at the American Association for Cancer Research annual meeting and simultaneously published in the New England Journal of Medicine.

Conducted in 834 patients with advanced melanoma (two thirds of whom were treatment-naive), the results show a significantly prolonged progression-free survival and overall survival as well as a milder side-effect profile for pembrolizumab compared with ipilimumab.

"This study clearly demonstrates the superiority of the PD-1 inhibitor compared to the CTLA-4 inhibitor," said Anthony Olszankski, MD, RPh, from the Fox Chase Cancer Center, in Philadelphia, Pennsylvania, who was not involved in the study, in comments to Medscape Medical News. "It was an absolutely necessary trial."

"We think these data should change the paradigm of treatment of these patients," said lead author Antoni Ribas, MD, PhD, from the University of California, Los Angeles, Jonsson Comprehensive Cancer Center.


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