FDA Approval Expands Immunotherapy Options for Advanced Melanoma

On Saturday, the FDA expanded the role of immunotherapy cancer treatments yet again, by approving the combination of two immunotherapy drugs—nivolumab (Opdivo®) and ipilimumab (Yervoy®)—as a frontline treatment for advanced melanoma regardless of mutational status.

Previously, the combination of these two drugs, both of which are manufactured by Bristol-Myers Squibb, had only received approval for patients whose melanoma lacked a specific mutation in the BRAF V600 gene. Saturday’s decision makes this effective combination treatment available for all previously untreated patients with advanced melanoma, and will enable improved outcomes in even more patients.

The accelerated approval for this combination was based on preliminary results from the phase III trial CheckMate-067. In this study, patients were given either: 1) nivolumab and ipilimumab in combination; 2) nivolumab alone; or 3) ipilimumab alone. According to all clinical metrics, the combination therapy led to improved responses in patients over both of the monotherapies.

Let’s look at the science behind these treatments. Both of these drugs belong to a class of immunotherapies known as checkpoint inhibitors. During cancer progression, tumor cells may develop the ability to evade the immune response through PD-1. Additionally, CTLA-4 can reign in the immune system’s response to cancer. To counter this, nivolumab blocks PD-1 activity and ipilimumab blocks CTLA-4 activity, and together enable the immune system to continue its attack. By empowering the immune response from complementary angles, the combination of nivolumab and ipilimumab made it harder for the cancer to disrupt and outsmart the immune response, leading to enhanced anti-cancer activity and improved patient responses.

Patients receiving the combination had a median progression-free survival of 11.5 months, compared to 6.9 months for nivolumab alone and 2.9 months for ipilimumab alone. Additionally, the objective response rate—complete responses plus partial responses—was 50% for patients receiving the combination therapy, compared to 40% for nivolumab alone and 14% for ipilimumab alone.

Many experts believe that these combination immunotherapies hold the key to maximizing immunotherapy’s effectiveness. They applaud the ability of both the regulatory and scientific communities to rapidly translate insights in the lab into lifesaving medicine for late-stage patients who don’t have the luxury of waiting several years for approval.

“This example actually shows that drug development doesn’t necessarily require enormous studies with many years of follow-up,” said the trial’s lead investigator, Jedd D. Wolchok, MD, PhD, an associate director of the Cancer Research Institute’s Scientific Advisory Council chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Center. “It’s possible to move at a much faster pace when everyone is collaborating effectively,” he added.

Importantly, patients who received nivolumab alone had better responses compared to those who received ipilimumab alone. This led to the FDA additionally approving nivolumab alone for frontline treatment of all previously untreated patients with advanced melanoma. Before, nivolumab was approved only for previously untreated melanoma patients without the BRAF mutation.

While accelerated approval was based on preliminary progression-free survival, the CheckMate-067 study remains ongoing, and patients continue to be followed for overall survival in addition to other responses.