FDA Approval of Pembrolizumab Brings New Hope in Melanoma

September 5, 2014
Christina Izzo

The FDA has approved pembrolizumab (Keytruda) for the treatment of advanced melanoma, making it the first PD-1 inhibitor to receive approval in the United States and marking yet another milestone breakthrough for patients who once had little hope of surviving this disease.

Tim Turnham

The FDA has approved pembrolizumab (Keytruda) for the treatment of advanced melanoma, making it the first PD-1 inhibitor to receive approval in the United States and marking yet another milestone breakthrough for patients who once had little hope of surviving this disease.

“This drug has higher response rates with lower toxicities than any other melanoma drug available to patients right now,” Tim Turnham, executive director of the Melanoma Research Foundation, said in an interview. “And I can tell you that the melanoma patient community has been waiting for this day anxiously because they know that this drug offers great promise.”

The accelerated approval was based on response rates demonstrated in clinical trial data from 173 patients with melanoma in the KEYNOTE-001 study. At the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate (ORR) was 24%, with a response duration lasting from 1.4 to 8.5 months.

Pembrolizumab is a humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1. The agent binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell—mediated immune responses against tumor cells.

A More Tolerable Safety Profile

The only other checkpoint inhibitor approved in this space is ipilimumab, which was approved in March 2011.

“That at the time was a great breakthrough,” Turnham said. “It was the first new drug approved for melanoma in 13 years. It has saved a lot of people’s lives and there are people who are now 10 years cancer free because of that drug.”

However ipilimumab, a CTLA-4 inhibitor, came with some toxicity issues, Turnham said. This caused patients to be wary about taking the drug and even stopped some physicians who weren’t familiar with ipilimumab from prescribing the drug to patients.

PD-1 inhibitors seem to be more tolerable, Turnham said.

The safety profile for pembrolizumab was established based on data from 411 patients enrolled in various studies. The most common side effects were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea, according to the FDA.

Across the 411 patients, pembrolizumab was discontinued as a result of adverse reactions in 9% of patients. At the 2 mg/kg dose, the discontinuation rate was 6%. Immune-mediated adverse reactions included pneumonitis (2.9%), colitis (1%), hepatitis (0.5%), hypophysitis (0.5%), nephritis (0.7%), hyperthyroidism (1.2%), and hypothyroidism (8.3%).

Turnham stressed that patients should be transparent when discussing with nurses and physicians their side effect symptoms because immunotherapy-related adverse events can be addressed effectively if they’re caught early.

“It’s critically important that patients communicate any change or any hint of a symptom early on,” he said.

Because some patients will try to hide their symptoms for fear that they’ll be taken off the drug, Turnham said it is important that oncology nurses create a good dialogue with their patients about side effects.

“The oncology nurses are the key to this communication,” he said. “The patients will be more comfortable conveying [side effect] information to oncology nurses than to oncologists and physicians.”

Looking Ahead

While there is a lot of excitement about pembrolizumab, Turnham said that the response rates are nothing close to 100%, and work still needs to be done in this field.

“We want people to be hopeful, but not to be naïve that this is a magic cure for everyone,” he said. “We still have work to do.”

Turnham said there is a lot of room for exploration in the immune checkpoint area in the field of melanoma.

“We will see even more promise when we begin combining [PD-1 inhibitors] with other drugs,” he said. “I think we’ll see synergies that will make the combination better than either drug would have been by itself.”

Bristol Myers Squibb’s PD-1 agent, nivolumab, is being studied in combination with ipilimumab. The data, which was presented at the 2014 ASCO Annual Meeting, showed a 40% objective response rate in 53 patients with advanced melanoma and a preliminary overall survival (OS) of 80%.

There is also an ongoing clinical trial planned to investigate T-VEC, an oncolytic vaccine, in combination with pembrolizumab in previously untreated advanced melanoma.

Turnham said researchers are also interested in combining pembrolizumab and other immunotherapies with BRAF inhibitors.

The new and changing combinations will provide future challenges for nurses managing toxicities, Turnham said.

“As we do these combinations, we will continue to see unique adverse event profiles and we’ll need oncology nurses to be particularly astute around these things…in order to catch them early,” he said.

But with the approval of these new agents, oncology nurses working in the melanoma field will start to see a brighter future for their patients.

“Oncology nurses who have been working in the melanoma space, particularly those that have been in the space a while and are accustomed to having an almost constant litany of patients coming into their care and dying, will begin to see a significantly different outcomes, and they’ll begin to have better stories,” Turnham said. “The future definitely looks brighter today than it did yesterday.”