If cancer exhibits a weakness, exploit it before taking the target away. That's what researchers did in a Phase II randomized clinical trial showing that adding immunotherapy before surgical removal of Stage III-IV melanoma significantly improved event-free survival and produced no more side effects than standard-of-care treatment, which provides immunotherapy only after surgery. Results of the multicenter trial, led by a team that included researchers from the UCLA Jonsson Comprehensive Cancer Center were published in the New England Journal of Medicine (2023; doi: 10.1056/NEJMoa2211437).
"This is the first clinical trial demonstrating that neoadjuvant therapy-that given before surgery-is superior to the same therapy given in the adjuvant setting after surgery," said Antoni Ribas, MD, PhD, Director of the Tumor Immunology Program at UCLA Jonsson Comprehensive Cancer Center and the paper's senior author. "This is because it is best to turn on the immune system inside the cancer before it is taken out with the surgery."
The researchers designed the study and treatment regimen on how pembrolizumab used in this study and similar drugs called immune checkpoint inhibitors are thought to work. The antibody pembrolizumab is a PD-1 inhibitor; it blocks an immune checkpoint that blunts the immune system's response to cancer. The therapy releases the antitumor immune response-often referred to as "taking the brakes off the immune system"-enabling immune cells already existing at the tumor site to proliferate and attack the cancer cells at that place or anywhere else in the body.
"Based on this understanding, removing the bulk of the tumor, along with the tumor-infiltrating immune cells contained in the surgical specimen, is likely to take away some or even most of the potential antitumor immune cells that would proliferate after PD-1 blockade," said Ribas, Chair of the SWOG Cancer Research Network's melanoma committee when the study was designed and launched. "Our theory has been-and this study confirms it-that starting anti-PD-1 blocking therapy before surgery could activate more antitumor immune cells and improve clinical outcomes compared with the same amount of drug delivered after the surgery."
According to first author Sapna Patel, MD, "It's not just what you give, it's when you give it." She is Chair of the SWOG Cancer Research Network's Melanoma Committee and Associate Professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.
Study Details
The trial included patients with clinically detectable, measurable Stage IIIB-IVC melanoma that could be surgically resected. Patients were randomly assigned to one of two groups. Those in the adjuvant therapy group, consisting of 159 patients, were treated with surgery followed by pembrolizumab given every 3 weeks for a total of 18 infusions. The 154 participants in the neoadjuvant group received three infusions of pembrolizumab before surgery, followed by the remaining 15 infusions after surgery. Therefore, both study groups received the same drug and the same total number of 18 infusions, with the only difference being the timing of surgery.
The researchers found that at 2 years 72 percent of patients in the group receiving neoadjuvant pembrolizumab followed by adjuvant pembrolizumab were free of events (i.e., inability to get surgery, recurrence of the melanoma, or death) compared to 49 percent of the patients in the adjuvant pembrolizumab alone group.
Bartosz Chmielowski, MD, Clinical Professor of Medicine in the Division of Hematology-Oncology at UCLA and study co-author, said the research findings could change the way high-risk melanoma is routinely treated.
"The study highlights that the timing of administration of an immune checkpoint inhibitor relative to surgery can have a large effect on patient outcomes, even though the same systemic therapy was given to both study groups," he explained. "Our results demonstrate a significant benefit when immunotherapy is started prior to surgery to generate an immune response while the bulk of the cancer and the anti-tumor immune cells remain intact."