What was the study design, and what key objectives were evaluated in ADAM?
In terms of the design, we designed it as a rigorous trial with phase 3 statistics. It’s a randomized, double-blinded, placebo-controlled trial. We [randomly assigned] 100 patients total, in a 1:1 ratio, to either avelumab or placebo. For the avelumab treatment, we used a dose de-escalation schema, where patients got avelumab every 15 days for the first 4 months, then the frequency was reduced to every 30 days for the next 4 months. Following the first 8 months, where we thought the risk of recurrence was highest, we further de-escalated to every 4 months to time the infusions with the timing of the scans. [We then] followed patients every 4 months with scans for the first 2 years, every 6 months for the next 3 years, and after that, we’ve left it to investigator discretion. The primary end point of the trial is RFS, although we looked at a lot of secondary end points, including overall survival, distant [metastasis]–free survival, and safety end points as well.
ADAM Trial in Merkel Cell Carcinoma: Key Highlights
- Adjuvant avelumab numerically improved 1-year RFS vs placebo (87.2% vs 59.6%; stratified, age-adjusted HR, 0.55; 95% CI, 0.28-1.06; P = .075) in patients with high-risk stage III Merkel cell carcinoma.
- In exploratory analysis, avelumab reduced the risk of relapse alone by nearly half (stratified, age-adjusted HR, 0.47; 95% CI, 0.24-0.95), with a 28% absolute risk reduction at 1 year.
- MCC-specific survival was 92% across the full cohort, suggesting patients who relapsed on placebo were effectively salvaged with subsequent immunotherapy.
Is there a “sweet spot” for the duration of adjuvant immunotherapy across cancer types?
In skin cancers, most trials of adjuvant therapy have used 1 year of immune checkpoint blockade. To be honest, we don’t know what the sweet spot is. We think that the majority of the benefit from adjuvant therapy comes in the first few months when the risk of recurrence is highest, but we don’t know how long we need to keep treating to maintain that initial benefit. It’s an open question for the field, and unless we do dedicated trials, which are focused on the duration of therapy, we are probably not going to have a definitive answer on that.
What key findings from the ADAM trial were presented at ASCO 2026, and what stood out most?
For the ADAM trial, first of all, this major academic collaboration was done without a CRO or a cooperative group. The first message is that investigator-initiated research of the highest rigor can be accomplished with relatively limited resources, and I credit our amazing team at the University of Washington and also our academic collaborators who have come together to answer an important question in the field.
In terms of the main results, I’ll first talk about safety. We did not see any new safety signal that we haven’t seen previously with immune checkpoint inhibitors in the adjuvant setting. The toxicity of avelumab was pretty much as we would expect, with close to a 15% rate of treatment-related grade 3 or higher adverse effects [TRAEs], and around 7% to 8% of patients discontinuing treatment due to [a TRAE].
In terms of the efficacy end points, our primary end point was [RFS]. There was a clear impact of avelumab on the biology of recurrences [compared with] the placebo group, as we had expected. This was a high-risk setting, and there was around a 40% rate of relapse in the placebo group. Most of those relapses happened in the first year. In the avelumab group, there was a clear separation of the 2 curves: after the first year, only 12% of patients had relapsed in the avelumab group, compared [with] 40% in the placebo group, which suggests an absolute risk reduction of 28%––impressive for any adjuvant trial. What we also noticed is [that] in the avelumab arm, there were some late recurrences happening; we had some recurrences in the second year and the third year, but then after that, the curve seemed to stabilize.
One thing that affected the primary end point to some degree is that the avelumab arm was, on average, 5 years older [than] the placebo arm. That probably accounted for some non–cancer-related deaths happening, and as you know, RFS is a composite end point of relapse as well as survival. Those non-MCC deaths seem to bring down the RFS curve somewhat in the avelumab arm. Despite that, our [HR] was an impressive 0.55 with a P value of .07, which does not quite meet the level of statistical significance, but we feel that the results are going to be meaningful in the clinic.
We also did an exploratory analysis of relapse only, and that suggests an [HR] of 0.47 and around a 50% reduction in the risk of relapse over a patient’s journey. We also looked at other secondary end points like distant [metastasis]–free survival, which also seems to be favoring the avelumab arm, although the numbers, as you would expect, are lower compared to the overall relapse.
