Citation
Miller DM, Strong J, Emerick KS, Gupta S, Silk AW, Brownell I. Adjuvant anti–PD-1 for Merkel cell carcinoma: Ready for the clinic? Journal of Cutaneous Oncology. 2023;1(2). doi:10.59449/joco.2023.09.11.
Why this article mattered
Immune checkpoint inhibitors had already transformed advanced Merkel cell carcinoma, making postoperative treatment an obvious next question. ADMEC-O was the first randomized trial to report whether adjuvant nivolumab could reduce recurrence after complete resection.
The trial suggested a clinically meaningful disease-free survival benefit, but uncertainty around statistical precision, radiation use, toxicity, and patient selection prevented the results from establishing a new routine standard.
ADMEC-O provided an encouraging signal that adjuvant nivolumab can reduce recurrence after resection of MCC. It did not establish that every patient with resected disease should receive one year of postoperative immunotherapy.
ADMEC-O at a glance
Patients with completely resected MCC
Participants were randomized 2:1 to nivolumab for one year or observation.
Nivolumab versus observation
The absolute difference favored adjuvant treatment, although confidence intervals crossed no effect.
Cox hazard ratio
The estimate favored nivolumab but remained statistically imprecise.
What the trial suggests
- Postoperative nivolumab may reduce recurrence after complete resection.
- The magnitude of benefit appeared clinically meaningful at both 12 and 24 months.
- The findings were biologically plausible given the activity of PD-1 and PD-L1 blockade in advanced MCC.
- Patients with both earlier- and later-stage disease appeared to derive a disease-free survival signal.
- The trial established an important foundation for later adjuvant studies in MCC.
Why the study did not settle practice
Statistical uncertainty
The study was exploratory, the primary endpoint was descriptive, and no formal hypothesis test established a definitive treatment effect.
Radiation imbalance
Postoperative radiation was used more often in the observation group than in the nivolumab group, complicating interpretation of the treatment effect.
Treatment burden
Grade 3–4 adverse events occurred in 42% of nivolumab-treated patients, compared with 11% under observation.
Overall survival remained unknown
The central question—whether treating microscopic disease improves survival compared with treating recurrence early—was not answered.
The trial justified further study and serious discussion, but not routine use. A recurrence signal alone was not enough to outweigh uncertainty about overtreatment, immune toxicity, radiation, and the absence of mature survival data.
What the Journal Club revealed
Despite the favorable numerical results, no surveyed clinician reported that ADMEC-O would immediately change their practice. When presented with a patient with clinical stage III MCC, none selected a strategy that directly reproduced the trial’s experimental approach.
- Clinicians viewed the study as important but not practice defining.
- Clinical-trial enrollment remained the preferred strategy when available.
- Postoperative radiation continued to play a major role in resected MCC management.
- Many providers were concerned about treating patients already cured by surgery and radiation.
- Regulatory labeling and payer coverage were expected to limit off-label implementation.
Adjuvant or neoadjuvant immunotherapy?
Even as ADMEC-O evaluated postoperative therapy, emerging data suggested that immunotherapy may be more effective when macroscopic tumor remains present. Preoperative treatment offers the possibility of greater antigen exposure, direct assessment of pathologic response, and earlier identification of patients with resistant disease.
In CheckMate 358, two doses of neoadjuvant nivolumab produced a major pathologic response in 61.5% of patients with resectable stage II–IV MCC. These findings raised the possibility that an adjuvant-only strategy might not be the optimal way to deploy checkpoint blockade in resectable disease.
ADMEC-O opened the door to adjuvant anti–PD-1 therapy but did not close the debate. The enduring question is not simply whether postoperative immunotherapy reduces recurrence, but when immunotherapy should be given, to whom, and whether earlier treatment improves outcomes enough to justify exposing more patients to toxicity.
What came next
- Longer follow-up from ADMEC-O.
- Results from additional adjuvant trials, including ADAM and STAMP.
- More precise natural-history estimates for contemporary resected MCC.
- Prospective comparisons of neoadjuvant, perioperative, and adjuvant-only strategies.
- Biomarkers capable of identifying patients most likely to recur and most likely to benefit.
Authors
David M. Miller, Jennifer Strong, Kevin S. Emerick, Sameer Gupta, Ann W. Silk, and Isaac Brownell.