Merck’s PD-1 Drug Outperforms Ipilimumab for Treatment of Advanced Melanoma

For melanoma patients, it was a very big deal in 2011 when the FDA approved the CTLA-4 blocking antibody ipilimumab (Yervoy®) for the treatment of advanced melanoma. “Ipi” was the first drug ever to improve survival for advanced melanoma in a phase III study. About 20% of patients respond to ipi, and some of the earliest patients treated with the drug are now 10 years out and still free of disease.

The success of ipilimumab was about more than the triumph of an individual drug. It also validated a new and powerful approach to cancer immunotherapy. Known as checkpoint blockade, this approach uses drugs (typically antibodies) to “release the brakes” on immune cells, empowering them to launch a stronger attack against cancer. It was the brainchild of James P. Allison, PhD, director of CRI’s Scientific Advisory Council, based on work he did in the late 1990s and early-2000s while a professor at UC-Berkeley. Ipi was the first checkpoint inhibitor to prove the efficacy of this approach.

In the years since ipi appeared on the scene, a number of new checkpoint inhibitors have been developed which target other immune checkpoints, including a molecule on T cells called PD-1. Several different PD-1-blocking drugs are currently being produced by several different pharmaceutical companies. The first to receive the green light from the FDA was Merck’s drug pembrolizumab (Keytruda®), which was approved in September 2014 for the treatment of advanced melanoma that had stopped responding to other drugs, including ipilimumab.

Keytruda achieved “a statistically significant and clinically meaningful improvement in overall survival and progression-free survival compared to ipilimumab.”

Now for the big news: today, Merck announced that the results from a phase III trial indicate that Keytruda is more effective than ipilimumab as first-line treatment for melanoma. The trial, called KEYNOTE-006, will be stopped early because Keytruda achieved “a statistically significant and clinically meaningful improvement in overall survival and progression-free survival compared to ipilimumab,” according to a company press release. The full results of the trial will be presented in April at the upcoming meeting of the American Association for Cancer Research (AACR) in Philadelphia.

What does this mean for patients? Well, there are several possibilities. If the data are validated and the FDA approves Keytruda for the first-line treatment of melanoma, it could mean that ipi is no longer the standard of care for this indication. Whether ipi is still used will depend on several other factors, including the results of studies that are looking at ipilimumab in combination with other drugs.

The drug maker Bristol-Myers Squibb is currently testing a combination of ipilimumab and nivolumab (its anti-PD-1 drug) for the treatment of advanced melanoma, and the results so far have been impressive: nearly 90% of patients treated at the best-responding dose were still alive at 2 years, compared to a historical 2-year survival rate of 15% with conventional therapies. These results could provide a rationale for using ipilimumab as one part of an overall strategy to treat melanoma. Stay tuned for more this front.

Looking backward at the excitement that greeted ipilimumab, and forward to the possibility of even more effective immunotherapy drugs for melanoma, it’s clear that we are indeed making progress against this deadly disease. Ipi may have been the first big success story for cancer immunotherapy, but it surely won’t be the last.