Published on September 24, 2021
Patients With Stage II Melanoma Benefit From Immunotherapy After Surgery
A new treatment regimen may be on the way for patients with high-risk stage II melanoma. According to results from the phase 3 KEYNOTE-716 trial, shared during the European Society of Medical Oncology (ESMO) Congress 2021, patients with stage IIB and IIC melanoma who received the immunotherapy drug pembrolizumab (Keytruda) after surgery had a 35% lower risk of death or recurrence than patients who received a placebo.
“These results are set to substantially change the population of melanoma patients who get treated in the adjuvant setting,” said lead study author Jason J. Luke, MD, Director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center in Pittsburgh, during his presentation at the ESMO meeting.
Adjuvant therapy is cancer treatment given after primary therapy to reduce the chance of the cancer coming back. It often includes chemotherapy, hormone therapy, radiation therapy, or immunotherapy to destroy any remaining cancer cells. Currently, most patients with stage II melanoma do not receive adjuvant therapy after surgery.
“There has been a belief that early-stage melanoma doesn’t recur very fast and that these patients don’t develop metastatic disease,” Dr. Luke explained. “These data clearly disprove that and show that patients with high-risk stage II melanoma recur quickly and distantly, just the same as patients with stage IIIA and IIIB. Treatment with pembrolizumab reduced that in a meaningful and statistically significant way, indicating that these stage II patients should be offered adjuvant therapy.”
How Does Pembrolizumab Work?
Pembrolizumab is a type of immunotherapy known as a checkpoint inhibitor. It helps the immune system fight cancer cells by blocking the activity of a protein called PD-1, which prevents T cells (a type of white blood cell) from recognizing and attacking cancer cells. Once pembrolizumab inhibits PD-1, the immune system can better attack and destroy melanoma cells. Pembrolizumab is given intravenously (into a vein) and is now approved by the U.S. Food and Drug Administration (FDA) to treat more than a dozen cancer types.
The KEYNOTE-716 Clinical Trial
Researchers randomly assigned 976 patients to receive either pembrolizumab or a placebo once every three weeks for up to one year. To participate, patients had to be at least 12 years old and have been diagnosed with stage IIB or IIC melanoma. The patient profile in both groups was similar: the median age was 60, gender skewed slightly male (60%), and tumor depths were 3b, 4a, or 4b.
The primary endpoint of the trial was recurrence-free survival (RFS). That measures the length of time a patient survives after treatment without any signs or symptoms of cancer. Dr. Luke and his colleagues planned to assess patients every six months for four years and then a final time in year five. Data showed a statistically significant difference after just one year, with pembrolizumab prolonging RFS substantially compared with the placebo.
“KEYNOTE-716 met its primary endpoint of relapse-free survival,” said Dr. Luke, sharing the 12-month data. In the pembrolizumab arm, 90.5% of patients had neither relapsed nor died at the one-year point, compared to 83.1% of patients in the placebo arm. Although the trial hit its primary endpoint early, Dr. Luke and his team will continue monitoring the patients. He expects the gap between the groups to widen over time, further establishing the efficacy of pembrolizumab.
“We will continue to see these data mature, and in fact, it is our full expectation that these curves will continue to separate over time,” he said.
Pembrolizumab Side Effects
When considering adjuvant therapy, the long-term management of side effects is an important consideration. Patients in both the placebo and pembrolizumab group reported adverse events typically associated with immune checkpoint inhibitors including diarrhea, fatigue, nausea, and pruritis (itching). However, patients in the pembrolizumab arm reported more treatment-related adverse events. This included an elevated risk of developing hyperthyroidism or hypothyroidism. Dr. Luke explained that patients with cancer are more prone to thyroid events than those without cancer regardless of treatment type, and healthcare providers can help manage these effects.
“Within thyroid events, we see this group of patients who had thyroid events despite the placebo treatment, suggesting that even in the background for normal patients in this monitoring period of a clinical trial, a rate of about 4% to 5% of thyroid-based events would be expected,” he said. In the pembrolizumab group, 15.7% of patients experienced hypothyroidism and 10.4% hyperthyroidism. In the placebo group, the numbers were 3.5% and 0.6%, respectively.
What Do Patients With Melanoma Need to Know About Pembrolizumab?
The FDA first approved pembrolizumab in 2014 for patients with advanced melanoma whose cancer had progressed after certain other treatments. In 2019, the agency approved it as an adjuvant treatment for patients with stage III melanoma who still had evidence of the disease in their lymph nodes after surgery. Dr. Luke expressed optimism that this trial will help experts identify how best to use pembrolizumab to help patients with high-risk stage II melanoma.
“In a world of financial constraints and personalized medicine, we’d ultimately like to know exactly who we need to treat,” he said. “This trial provides a platform from which to do [that]. In addition, as patients who recur in the placebo arm cross over to the pembrolizumab group, we will eventually get an answer about whether it is more effective to treat right after surgery or to wait until the melanoma comes back.”
Dr. Luke also explained that while oncologists have historically defined high-risk melanoma patients as those who still have evidence of the disease in their lymph nodes after surgery, this trial may change that. Looking ahead, he said that the depth of the primary tumor and the ulceration status of the tumors should be considered along with the cancer stage when experts are deciding which therapies to offer patients.
The results of the trial sound promising to T.J. Sharpe, a patient advocate who was diagnosed with stage IB melanoma at age 25 and with stage IV melanoma at 37.
“Keeping an early-stage melanoma from recurring as a later-stage melanoma would be a huge advancement in the melanoma community,” Sharpe said. “Patients would be able to choose a proactive course of treatment with tolerable side effects as an option, instead of just being diligent with follow-up in hopes of catching a recurrence before it is too widespread.”
See Our Sources
- European Society of Medical Oncology Congress (2021). “Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma.”
- U.S. Food and Drug Administration (2019). “FDA approves pembrolizumab for adjuvant treatment of melanoma.”