Cutaneous melanoma is a severe form of skin cancer, and patients with Stage III or IV melanoma who have undergone surgical excision are at high risk of relapse. Previous randomized trials have shown that adjuvant therapy with programmed death 1 (PD-1)-blocking antibodies benefits these patients compared with no treatment or previous standard care adjuvant therapies (Cancer Discov 2022; https://doi.org/10.1158/2159-8290.CD-21-1141).
Additionally, it has been suggested that neoadjuvant treatment with PD-1 inhibitors (nivolumab or pembrolizumab) may activate more antitumor T cells and improve outcomes (Nature 2014; https://doi.org/10.1038/nature13954).
Recently, a randomized, Phase II, open-label trial was conducted by researchers from the Southwest Oncology Group (SWOG) Cancer Research Network to determine if administering anti-PD1 therapy before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy) increases event-free survival compared to pembrolizumab given as adjuvant therapy alone in patients with resectable Stage III or IV melanoma. The results of the trial were published in the New England Journal of Medicine, led by Sapna P. Patel, MD, and colleagues from the University of Texas MD Anderson Cancer Center (2023; doi: 10.1056/NEJMoa2211437).
The hypothesis of the researchers was that administering pembrolizumab therapy before surgery in patients with Stage III or IV melanoma would result in a stronger anti-tumor immune response and longer immunologic memory compared to administering it after surgery when the immune system would primarily respond to micrometastatic cancer cells.
The randomized multi-center study (NCT03698019) enrolled 313 patients (>=18 years) who had histologically confirmed cutaneous, acral, or mucosal melanoma; clinically detectable, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST); and Stage IIIB-IIID melanoma or oligometastatic resectable Stage IV (M1a, M1b, and M1c) melanoma.
Participants were randomly assigned 1:1 to receive neoadjuvant pembrolizumab at 200 mg every 3 weeks for 3 doses and adjuvant pembrolizumab at 200 mg every 3 weeks for 15 doses (n=154) or adjuvant pembrolizumab alone at 200 mg every 3 weeks for 18 doses (n=159). The primary endpoint of the trial was event-free survival (EFS), which included postsurgical recurrence events, disease progression, and toxic effects before adjuvant therapy initiation. The study also evaluated safety and allowed postoperative radiotherapy at the investigator's discretion, but not concomitant administration with pembrolizumab.
The median follow-up duration of 14.7 months revealed that the neoadjuvant-adjuvant group consisting of 154 patients had a notably longer EFS than the adjuvant-only group comprised of 159 patients (P=0.004 by the log-rank test). Moreover, it was found that the percentage of patients with EFS at 2 years was 23 percent higher in the neoadjuvant-adjuvant therapy arm compared to the adjuvant therapy arm, with EFS occurring in 72 percent (95% CI: 64-80) and 49 percent (95% CI: 41-59) of patients, respectively.
Regarding safety, in 7 percent of patients undergoing neoadjuvant therapy, treatment-related adverse events (AEs) of Grade 3 or higher occurred, with increased alanine aminotransferase (ALT) being the most frequent (3 patients). During adjuvant therapy, the occurrence of treatment-related grade 3 or higher AEs was reported in 12 percent of patients in the neoadjuvant-adjuvant group and 14 percent in the adjuvant-only group. The most common AEs observed in the neoadjuvant-adjuvant group were increased ALT and increased aspartate aminotransferase (AST), with two patients experiencing each. In the adjuvant-only group, the most common AEs were increased ALT, increased AST, and fatigue, with two patients experiencing each.
Oncology Times chatted with lead study author, Sapna Patel, MD, for her insights into the research. She is Associate Professor, Director of the Uveal Melanoma Program, and Melanoma Fellowship Program Director at the University of Texas MD Anderson Cancer Center. She also leads several cutaneous melanoma projects with SWOG and serves as Melanoma Chair for SWOG.
Oncology Times: Can you explain the mechanism of action of pembrolizumab and how it affects the immune system to fight melanoma?
Patel: "Anti-PD-1 checkpoint inhibitors work by blocking an immune checkpoint on the surface of T cells, releasing the T cells to eliminate a given target. Response to these therapies requires the presence of pre-existing antitumor T cells in contact with cancer cells being inhibited by the reactive expression of immune checkpoints such as PD-L1.
"Adjuvant anti-PD-1 therapy can activate only small populations of antitumor T cells against microscopic residual cancer. In contrast, the administration of anti-PD-1 blockade as therapy before surgery in the neoadjuvant setting induces an immune response from a larger population of T cells that reside in the bulk of the intact macroscopic tumor. Inhibiting the PD-1/PD-L1 immune checkpoint before surgery can induce a systemic antitumor immune response at local and distant sites before resection of the tumor bed. This approach is hypothesized to leave behind larger numbers and a more diverse population of antitumor T cells. These T cells can then be activated and circulated systemically to recognize and attack microscopic cancer cells after surgical removal of the tumor."
Oncology Times: Were there any notable differences in event-free survival or adverse events between the two treatment groups (adjuvant-only vs. neoadjuvant-adjuvant) when the data were stratified by age, sex, or race?
Patel: "Event-free survival favored the neoadjuvant group in all key subgroups, including age, sex, performance status, LDH level, stage, ulceration of the primary melanoma, and BRAF mutation status. There were some subgroups with sample sizes that were too small to draw conclusions, such as patients with acral melanoma (five in the adjuvant group, four in the neoadjuvant group) and mucosal melanoma (four patients all in the neoadjuvant group)."
Oncology Times: Could this study serve as the basis for changing current clinical practice guidelines for the treatment of advanced melanoma?
Patel: "This is the first randomized study in melanoma to demonstrate the superiority of neoadjuvant immunotherapy over adjuvant immunotherapy. S1801 used the same regimen in both arms, simply resequencing the timing of pembrolizumab doses. As such, this cost-neutral neoadjuvant regimen can serve as the basis for changing clinical practice guidelines worldwide where adjuvant anti-PD-1 therapy is currently approved."
Oncology Times: Are there any ongoing or planned studies investigating the use of pembrolizumab in combination with other therapies for the treatment of melanoma?
Patel: "[Researchers are] currently running the KEYMAKER-U02 umbrella trial (NCT04305054) combining pembrolizumab with other agents in metastatic melanoma and moving some combinations to the neoadjuvant setting."
Dibash Kumar Das is a contributing writer.