Adjuvant therapy with Nivolumab (Opdivo) was feasible and safe and appeared to prolong disease-free survival (DFS) in patients with completely resected Merkel cell carcinoma (MCC), interim results from a randomized phase II trial indicated.

The immune checkpoint inhibitor reduced the relative risk of death or disease progression over a median 2-years of follow-up compared with observation alone (HR 0.58, 95% CI 0.30-1.12, P=0.10), with a median DFS that was not reached in the ADMEC-O trial.

Adjuvant nivolumab resulted in an absolute risk reduction of 9 percentage points (85% vs 77%) and 10 percentage points (84% vs 73%) for 1-year and 2-year DFS, respectively, corresponding to relative risk reductions of 39% (95% CI –18 to 66) and 38% (95% CI –18 to 65).

“Although the interim analysis of ADMEC-O strongly suggests a clinical benefit of nivolumab in this area of unmet medical need, the risk values must be interpreted cautiously given the wide range of CIs,” reported Dirk Schadendorf, MD, of the University Hospital Essen in Essen, Germany, and colleagues in The Lancet.

Moreover, with 10 deaths in the active treatment group and six in the observation group, survival rates “are not mature enough to draw conclusions,” the authors observed.

In explaining the rationale behind the study, the authors noted MCC is an immunogenic but aggressive skin cancer that after complete resection and radiation — the principle therapeutic approach — still has high relapse rates, with a 5-year recurrence rate of 40%.

“Therefore, strategies to improve the outcome of patients who usually relapse within the first 24 months following surgery or radiotherapy are of crucial relevance.”

Immune checkpoint inhibitors have emerged as effective treatment options for patients with metastatic MCC. Thus, Schadendorf and colleagues wanted to assess adjuvant immune checkpoint inhibition in completely resected MCC — a setting they pointed out does not have an established systemic standard-of-care.

In a commentary accompanying the study Philippe Saiag, MD, PhD, and Astrid Blom, MD, both of the Ambroise Paré Hospital in Paris, noted that this is the first published randomized trial of adjuvant immune checkpoint inhibition in MCC and “represents a milestone that will help to design future trials in this field.”

Yet, several issues need to be addressed before this strategy is used in the adjuvant setting, they added.

For example, more mature data are needed with longer-follow up, they said, as are results from ongoing trials in this population investigating adjuvant avelumab (Bavencio) or pembrolizumab (Keytruda).

Saiag and Blom also observed that, apart from nivolumab treatment, the protocol in this trial did not require similar managment in treatment and control groups. Furthermore, they noted the trial had a relatively low number of patients, lacked statistical power, and had hazard ratios that originated from a post-hoc analysis.

The study included 179 patients from 19 academic centers in Germany and one in the Netherlands. Of these patients, 65% had stage III/IV MCC, 68% were ≥65 years of age, and 62% were male. These factors were balanced between the nivolumab arm (118 patients) and the observation control group (61 patients).

Adverse events occurred in 97% of the 115 patients receiving at least one dose of nivolumab, while Adverse Events were recorded for 49% of the 61 patients in the observation group. Grade III/IV adverse events occurred in 42% of 115 patients who received at least one dose of nivolumab and seven (11%) of 61 patients in the observation group.

Schadendorf and colleagues said the patterns and frequencies of treatment-related adverse events were consistent with the tolerability and known side-effect profile demonstrated with PD-1 inhibitors; and that no new safety signals emerged from the trial.

However, they pointed out that 17 patients stopped nivolumab therapy due to treatment-related adverse events, with six of them due to grade III/IV events.