European Regulators Approve Pembrolizumab (Keytruda) as First-line Treatment of Advanced Melanoma

Today, regulators in Europe approved the immunotherapy drug pembrolizumab (Keytruda®) for the treatment of advanced melanoma. The decision was based on the results of three large clinical trials conducted in more than 1,500 patients, including an important phase III trial that showed a statistically significant improvement in survival for patients on pembrolizumab compared to ipilimumab, the current standard-of-care drug for advanced melanoma. On that trial, called KEYNOTE-006, patients receiving pembrolizumab (dosed every 2 weeks) had a 1-year overall survival rate of 74% compared to 58% for ipilimumab, and a 37% reduction in risk of death.

The decision by the European regulators makes pembrolizumab, made by the drug company Merck, the second PD-1-targeting drug to be approved in Europe. The PD-1 drug nivolumab (Opdivo®), made by Bristol-Myers Squibb, was approved there for the same indication in June of this year. 

Both pembrolizumab and nivolumab are immune drugs called checkpoint inhibitors that “release the brakes” on the immune system, allowing a stronger immune attack against cancer. The particular braking molecule they target is called PD-1. Both drugs are approved in the US as second-line treatment of advanced melanoma, after patients have been treated with ipilimumab or a BRAF inhibitor. In contrast to the situation in the US, in Europe the two PD-1 drugs are approved as both first- and second-line therapy.

It is likely only a matter of time before PD-1-targeting drugs are approved as first-line treatment of melanoma in the U.S., as several large clinical trials have now demonstrated the superiority of PD-1 drugs over ipilimumab as first-line treatment. And in fact, the National Comprehensive Cancer Network (NCCN), a non-profit alliance of the nation’s leading cancer centers that makes recommendations about treatment, in January of this year concluded that both pembrolizumab and nivolumab have “higher response rates and less toxicity compared to ipilimumab, and that both drugs should be included as options for first-line treatment.” The drugs are currently under review by the FDA, with a decision expected by August of this year (for nivolumab). 

In the likely event that both drugs are approved as first-line therapy in the US, which drug should patients seek and doctors prescribe? Available evidence suggests that both pembrolizumab and nivolumab have comparable efficacy—though a direct head-to-head test has not been conducted. The decision to use one drug over another, therefore, may come down to non-medical considerations, such as price. 

For some patients, the combination of ipilimumab and a PD-1-targeting drug (either pembrolizumab or nivolumab) may prove to be the best therapeutic choice. As CRI clinical director Jedd Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center presented at this year’s ASCO meeting, a large phase III trial showed that the combination of ipi + nivo can provide added therapeutic benefit to patients whose tumors are classified as PD-L1-negative. PD-L1 is the binding partner of the PD-1 checkpoint on immune cells. Emerging evidence suggests that patients with higher levels of PD-L1 in their tumors respond better to PD-1-blocking drugs. For patients with lower levels of PD-L1, treatment with ipilimumab, which targets a different immune checkpoint, may serve to increase the level of PD-L1 in tumors and therefore potentiate the response to PD-1 inhibitors.

For a list of current immunotherapy treatment options for patients with melanoma, and to see how the Cancer Research Institute is advancing science in this area, visit our webpage devoted to melanoma immunotherapy.