In a phase II, randomised study involving patients with resectable stage III or IV melanoma, the percentage of patients with event-free survival (EFS) at 2 years was 23% higher among those who received neoadjuvant pembrolizumab followed by adjuvant pembrolizumab than among those who received adjuvant pembrolizumab only. In the neoadjuvant–adjuvant group, disease progression or side effects resulting in an inability to undergo surgery occurred in less than 10% of the patients, and the overall incidences of grade 3 or 4 side effects were lower than those reported in studies of neoadjuvant immune checkpoint blockade combining anti–PD1 and anti–CTLA4. Findings from the S1801 study are published by Dr. Sapna P. Patel of the University of Texas M.D. Anderson Cancer Center Houston, TX, US and colleagues on 2 March 2023 in The New England Journal of Medicine.
Patients with stage III or IV melanoma who have undergone surgical excision remain at high risk for relapse. Three randomised studies showed that these patients derive benefit from adjuvant treatment with PD1 inhibitor, nivolumab or pembrolizumab, as compared with no treatment or previous standard of care adjuvant treatment, interferon-α2b or ipilimumab.
The clinical benefit of anti–PD1 in the adjuvant setting suggests that blocking the inhibitory PD1 immune checkpoint causes a systemic antitumour response, resulting in the elimination of melanoma micrometastases by antitumour T cells. It has been hypothesised that neoadjuvant treatment may be able to activate more antitumour T cells and improve clinical outcomes than administration of the same amount of drug delivered postoperatively.
To test whether administration of anti–PD1 before and after surgery would result in better outcomes than administration of the same treatment only after surgery, the Southwest Oncology Group (SWOG) Cancer Research Network performed S1801 study. In this phase II study, the investigators randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to 3 doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant–adjuvant group) or to surgery followed by pembrolizumab 200 mg intravenously every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurred or unacceptable side effects developed (adjuvant only group).
The primary endpoint was EFS in the intention-to-treat population. Events were defined as disease progression or side effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or side effects of treatment that precluded the initiation of adjuvant treatment within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.
At a median follow-up of 14.7 months, 154 patients in the neoadjuvant–adjuvant group had significantly longer EFS than 159 patients in the adjuvant-only group (p = 0.004 by the log-rank test). In a landmark analysis, EFS at 2 years was 72% (95% confidence interval [CI] 64 to 80) in the neoadjuvant–adjuvant group and 49% (95% CI 41 to 59) in the adjuvant-only group.
The percentage of patients with treatment-related adverse events of grades 3 or higher during treatment was 12% in the neoadjuvant–adjuvant group and 14% in the adjuvant only group. No new side effects were identified.
The authors underlined that their study shows that the timing of administration of an immune checkpoint inhibitor relative to surgery can have a large effect on patient outcomes. The results, combined with understanding of the mechanism of action of PD1 blockade, support the concept that neoadjuvant administration functionally inhibits the immune checkpoint before antitumour T cells are surgically resected.
The study was supported by grants from the US National Cancer Institute of the National Institutes of Health and in part by Merck Sharp and Dohme, a subsidiary of Merck.
Patel SP, Othus M, Chen Y, et al. Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 2023;388:813-823.